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",isbn:null,printIsbn:null,pdfIsbn:null,doi:null,price:0,priceEur:null,priceUsd:null,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"cc796459268324e827219d1d904e4265",bookSignature:"Prof. Moulay Tahar Lamchich",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/7196.jpg",keywords:"Induction motor, smart motor, electrical vehicles, energy generation, drives, electromechanical, hybrid transportation, smart control, high efficiency motor, variable speed drives, power electronic, energy efficiency.",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"July 4th 2018",dateEndSecondStepPublish:"July 25th 2018",dateEndThirdStepPublish:"September 23rd 2018",dateEndFourthStepPublish:"December 12th 2018",dateEndFifthStepPublish:"February 10th 2019",remainingDaysToSecondStep:"3 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"21932",title:"Prof.",name:"Moulay Tahar",middleName:null,surname:"Lamchich",slug:"moulay-tahar-lamchich",fullName:"Moulay Tahar Lamchich",profilePictureURL:"https://mts.intechopen.com/storage/users/21932/images/system/21932.png",biography:"Moulay Tahar Lamchich is a Professor at the Faculty of Sciences Semlalia at Marrakech (Morocco). He completed his thesis in electromechanics in September 1991 and received his third cycle degree. Dr. Lamchich received his Ph.D. from the same university in July 2001. His main activity is based on short-circuit mechanical effects in substation structures, control of different types of machine drives, static converters, active power filters. In the last decennia, his research interests have included renewable energies, particularly the control and supervision of hybrid and multiple source systems for decentralized energy production, and intelligent management of energy. He has published more than fifty technical papers in reviews and international conferences. With IntechOpen, he has published two chapters and was editor of the books “Torque Control” and “Harmonic Analysis”. He is also the director of the “Intelligent management of energy and information systems” laboratory and supervising more than ten thesis projects.",institutionString:"University Cadi Ayyad",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Cadi Ayyad University",institutionURL:null,country:{name:"Morocco"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"11",title:"Engineering",slug:"engineering"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"270941",firstName:"Sandra",lastName:"Maljavac",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/270941/images/7824_n.jpg",email:"sandra.m@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"37883",title:"The Role of Sodium-Calcium Exchanger in the Calcium Homeostasis of Airway Smooth Muscle",doi:"10.5772/47758",slug:"the-role-of-sodium-calcium-exchanger-in-the-calcium-homeostasis-of-airway-smooth-muscle",body:'ASM is a widespread component of the respiratory system. The lung parenchyma, like the airways, is a contractile tissue that responds to agonists like histamine and its muscular behavior highly impacts respiratory physiology. Asthma, for example, is a common disorder characterized by an excessive narrowing of the airways and inflammation in response to certain stimulants. Although the relative contribution of each element in this pathology is not precisely known, it is clear that smooth muscle relaxants alleviate acute asthmatic episodes. All of these points to ASM as an important target for study and therapy related to asthma.
The contractility of ASM highly depends on intracellular Ca2+ concentration and sensitization to Ca2+, which in turn depend on several transport and signaling mechanisms. Ca2+ homeostasis can be understood as a balance between Ca2+ entry and exit pathways governed by a dynamic web of physical and chemical signals. Ca2+ entry pathways in ASM include: voltage activated Ca2+ channels, non-selective cationic channels, IP3 activated Ca2+ channel and Ryanodine receptor-channel. On the other hand, Ca2+- ATPase pumps located in the plasma membrane and the Sarcoplasmic Reticulum account for the Ca2+ exit pathways. A very peculiar transporter, the Na+-Ca2+ exchanger (NCX), which is the main subject of this chapter, accounts for both Ca2+ exit and entry pathways due to its dual mode of operation. The many features and regulation of the NCX have been described mainly for the cardiac isoform which was the first to be cloned and characterized. Nevertheless, new research has been directed to other isoforms found in several tissues, including ASM, since a physiological role in contractility is now evident.
In this chapter, several aspects of ASM and the NCX will be addressed including: its role in Ca2+ homeostasis, contraction and proliferation; history of research related to the NCX; molecular and functional characteristics; and clinical implications.
As with other smooth muscles, cytosolic Ca2+ concentration underlies the most important features of ASM: contractility, proliferation and phenotype. Various complex mechanisms regulate cytosolic Ca2+ concentration and are strongly influenced by neurotransmitters, cytokines and physical forces, to name a few. Since the ASM cell interacts closely with tissues such as nervous terminals, epithelium and lymphocytes that secrete all such substances, it is not surprising that pathologies such as asthma and COPD are strongly linked to alterations in ASM Ca2+ homeostasis. In this section, the role of Calcium in contraction, phenotype acquisition and proliferation will be reviewed.
ASM contraction induced by agonist stimulation results mainly from two phenomena: elevation in cytosolic Ca2+ concentration and sensitization of the contractile machinery to Ca2+ [1]. This tissue is constricted directly by agonists such as histamine, cysteinylleukotrienes, thromboxanes and acetylcholine released by mast cells or airway nerves [2]. The primary signaling mechanism coupled to most contractile receptors is the activation of phospholipase Cγ (PLCγ) via a pertussis toxin-insensitive Gq/11-protein [3]. Activation of PLC leads to hydrolysis of phosphatidylinositol-bis-phosphate to inositol-1, 4, 5-trisphospate (IP3) and diacylglycerol (DAG) to, respectively, cause Ca2+ release from the sarcoplasmic reticulum (SR) and activate protein kinase C (PKC). It is known that prolonged stimulation by histamine causes intracellular Ca2+ increase in ASM strips which correlates with a sustained contraction [4]. As stated above, this is the sum of both sensitization and activation mechanisms involved in the contraction of smooth muscle.
Two key events in smooth muscle contraction are the phosphorylation and dephosphorylation of the regulatory light chains of myosin II (rMLC). These reactions are partly catalyzed by the Ca2+ and calmodulin-activated myosin light-chain kinase (MLCK) and the type 1 myosin phosphatase (MLCP), respectively. The balance of the activity of these enzymes results in the extent of contraction or relaxation of smooth muscle. After agonist stimulation, intracellular Ca2+ binds to calmodulin and changes its conformation, enabling it to activate MLCK. MLCK then phosphorylates rMLC, predominantly at Ser-19, allowing the myosin ATPase to be activated by actin. This leads to crossbridge formation between myosin and actin, and generates muscle contraction. The coupling between force and rMLC phosphorylation is quite variable and non-linear, however dephosphorylation of rMLC generally produces relaxation.
In addition to their effects of Ca2+ concentration changes, contractile agonists increase Ca2+ sensitivity of contraction. There are two ways to modulate such Ca2+ sensitivity: 1) altering the balance between the activities of MLCK and MLCP at a constant Ca2+ concentration, and 2) by rMLC phosphorylation-independent mechanisms as in the case of calponin, caldesmon and heat shock proteins.
MLCP is an heterotrimeric enzyme that contains a regulatory subunit referred to as the myosin phosphatase target subunit (MYPT) which helps to form the active heterotrimer as well as to increase the substrate specificity of MLCP toward myosin. This subunit is known to be phosphorylated by Rho Kinase becoming inhibited and thus favoring contraction. On the other hand, CPI-17 is an endogenous inhibitory protein of MLCP expressed in smooth muscle tissues which is itself regulated by RhoK and PKC phosphorylation [5-7].
On the other hand there are other mechanisms independent of phosphorylation of rMLC and pertain only to the thin filament actin. Calponin and caldesmon interact with F-actin and myosin and inhibit actomyosin ATPase activity. Both are regulated by PKC and ERK-activities [8, 9]. Altogether, the specific state of sensitization and intracellular Ca2+ concentration during agonist stimulation result in force development or relaxation of smooth muscle.
ASM remodeling is an important aspect of many atopic respiratory diseases. Among the structural changes that the airways undergo include epithelial fibrosis, increase in ASM mass, mucous gland hyperplasia and edema. Wall thickening due to ASM hyperplasia and hypertrophy are a common hallmark of asthma and constitute the mayor obstruction for air flow during a crisis. It is believed that these changes occur as a response to chronic airway inflammation and mechanical stretch in which ASM cells take an active role by migrating to the epithelium and secreting various adhesion molecules and cytokines. Airway remodeling is proposed to begin with ASM cell phenotype change from a contractile to a synthetic and migrating type. It is still not very clear how Ca2+ homeostasis is associated with the many features of ASM remodeling. It has been reported that the activity of CaV1.2 channels and the SERCA pump may underlie this process by an up-regulation of intracellular Ca2+. Downstream signaling mechanisms that lead to phenotype change include: Ca2+ /calmodulin-dependent protein kinase IV (CaMK.IV), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-α), nuclear respiratory factor-1 (NRF-1) and mitochondrial transcription factor A (mtTFA). Among these, mtTFA up-regulates mitochondrial DNA replication and biogenesis probably leading to ASM cell proliferation. Tissues from asthmatic patients tend to show increased intracellular Ca2+ levels, which may render ASM cells hyper-proliferative as well as hyperreactive to contractile stimuli [10, 11].
Ca2+ is a fundamental second messenger in the mechanisms of remodeling and contraction of smooth muscle cells. Under basal conditions, the intracellular Ca2+ concentration in smooth muscle cells ranges from 100 to 200 nM [6]. Upon activation by agonists such as acetylcholine or histamine, there is a biphasic intracellular Ca2+ response in ASM cells consisting of an initial Ca2+ rise followed by a fast decline to a steady-state level that remains above basal concentration until agonist is washed out [12]. This biphasic profile reflects the Ca2+ release from the SR as well as Ca2+ influx from the extracellular space. On the other hand, there are mechanisms that remove intracellular Ca2+ such as the Sarco/Endoplasmic Reticulum Ca2+-ATPase(SERCA), the plasmalemal Ca2+ ATPase (PMCA) and the mitochondria which become evident once agonist is removed and Ca2+ entry is abolished.
In airway smooth muscle, Ca2+ release from SR depends on IP3 and RyR receptor-channels [13, 14]. These channels belong to two different families and share significant homology, especially in the sequences that are proposed to form the channels´ pore. These Ca2+ release channels are large oligomeric structures formed by association of either four IP3R proteins (300 KDa each) or four RyR proteins (565 KDa each) [15-17].
The IP3R channel requires binding of IP3 for Ca2+ release with each monomer of the channel binding one molecule of IP3 in a non-cooperative fashion with a KD around 50 nM. An endogenous ligand for the RyR channels has remained elusive, and so far it has been proposed that in smooth muscle tissue, Ca2+ released by IP3R activates RyR channels; an event referred to as Ca2+ -Induced Ca2+ Release (CICR). Ca2+ release channels are regulated by various factors. Cytoplasmic Ca2+ shows a biphasic effect on the IP3 -induced Ca2+ release with a maximum rate at 300 nM. From that concentration on, the channel is inhibited by Ca2+. This inhibitory effect is also shared by the RyR channel, although it is not physiologically relevant, since millimolar concentrations of Ca2+ (1 – 10 mM) are required to inhibit the channel. Therefore, the Ca2+ release from the RyR channel shows only Ca2+-dependent activation in the physiological range of Ca2+ concentration (1 – 10 µM). Both channels are activated by free ATP, around 10 µM for the IP3R and 300 µM for the RyR channel.
An important modulator of the RyR channel is the plant alkaloid ryanodine which binds to each monomer with high affinity (Kd ‹ 50 nM). Low doses of ryanodine (around 10 nM) are reported to increase the frequency of single RyR channel opening. Intermediate ryanodine doses (around 1 µM) are reported to induce very long – duration open events and simultaneously reduce ion conductance through the pore. High doses of ryanodine (around 100 µM) are reported to lock the channel in a closed configuration.
The SR is continually re-filled with Ca2+ with the aid of the SERCA pumps located in its membrane. The SERCA are 110 kDa proteins that belong to the P-type ion pumps family. Their activity is a cycle of chemical reactions that lead to conformational changes and Ca2+ transport powered by phosphorylation. The activity of SERCA is largely regulated by phospholamban which in its phosphorylated state increases Ca2+ uptake. Even in the absence of an agonist, SR Ca2+ uptake appears to be critical for ASM basal tone maintenance. This has been explored in experiments where the SERCA pumps are inhibited by Cyclopiazonic acid (CPA) or Thapsigargin (TG) in resting smooth muscle. Under such conditions, ASM spontaneously contracts following an increase in intracellular Ca2+, which can be explained as a leak from the SR which cannot be handled by the impaired SERCA function. SERCA function is also evident when its inhibition is followed by incubation of ASM in Ca2+- fee solutions and agonist stimulation. Upon Ca2+ re-addition in these circumstances, a transitory contraction can be observed which is characteristic of a depleted SR and reflects the store-operated Ca2+ entry (SOCC) which is discussed below.
Besides the SR, the other source for Ca2+ in ASM is the extracellular media, but in this respect the involved mechanisms are unclear. Three main sources of Ca2+ have been proposed to be active in ASM: voltage activated CaV1.2 channels, transient receptor potential channels (TRP) and the NCX in reverse mode. The signaling mechanisms that activate each of these channels and transporters have not been completely understood, given that some of them have been just recently described in this tissue. Another interesting feature is the functional interaction among these systems as well as interactions with other channels such as the Ca2+-activated chloride channels (ClCa) and the Ca2+ activated potassium channels (BKCa). As will be discussed later, these channels regulate membrane potential and thus alter the activity of CaV1.2 channels, TRPC channels and the NCX. On the other hand, the ionic concentration reached within the vicinity of these channels upon stimulation, has also been observed to alter their function regardless of whole membrane potential.
It has been established that ASM membrane potential relies mainly on the activity of ClCa, BKCa and TRPC channels. ClCa and BKCa channels are activated by intracellular Ca2+ showing slightly different sensitivities between the ranges 100 to 900 nM [18, 19], and influence the membrane potential in opposite ways. ClCa channels allow Cl- to exit the cell, therefore depolarizing the membrane, while BK channels allow K+ to exit causing membrane hyperpolarization. It has been reported that Ca2+ released by the SR during histamine stimulation causes activation of ClCa channels and membrane depolarization [20]. TRPC have also been proposed to impact membrane potential at rest and after agonist stimulation causing depolarization. Histamine evokes an inward Na+ current in equine tracheal myocytes together with an outward Cl- current. In that work, it was suggested that NSCC of the TRPC family were responsible for the cationic current observed [21].
In many tissues, smooth muscle dihydropyridine-sensitive channels activated by membrane depolarization comprise an important source for external Ca2+ [22]. Interestingly, blockade of these channels has not served as a therapeutic tool in asthma, and thus their physiological relevance remains unclear. These channels are composed of pore-forming (α subunit) and accessory subunits that regulate expression, gating and channel kinetics. The α subunit carries the Ca2+ current and provides the voltage- and DHP-sensitivity of these channels [23]. Research has shown that voltage-related Ca2+ currents in ASM reflect CaV1.2 channel activity [12] which is the main isoform expressed in this tissue [24, 25]. Electrophysiological studies have found the threshold potential for these currents to be around -40mV and the peak activation between +10 and +20 mV. Although no precise value for resting ASM membrane potential has been described, several studies have reported values ranging between -60 and -30 mV [26, 27]. Thus, depolarization must occur before CaV1.2 channels could participate in agonist ASM induced contraction.
It has been reported that agonists like histamine and carbachol provoke a small and inward cationic current through non-selective cationic channels (NSCC) in tracheal smooth muscle of different species [28, 29].There is evidence that points to the transient receptor potential channels (TRP) as candidates for this conductance. TRP channels were first described in Drosophila melanogaster and then, homologues for these channels in at least 20 mammalian species were found to the point that almost all mammalian TRP channels are now known. Unlike most ion channels, TRP channels are identified by their homology rather than by ligand function or selectivity, because their functions are diverse and mostly unknown. The canonical (TRPC) subfamily of these channels comprises seven isoforms: TRPC1-7, and which have been detected in guinea pig and human ASM [30, 31]. It is generally accepted that TRPC channels are activated downstream by agonist-stimulated PIP2 hydrolysis, but still their exact mode of activation and operation is unclear. Both store-dependent and independent mechanisms of activation have been proposed, in cases, even for the same channel in different preparations. All mammalian TRPC channels can be activated by GPCRs including muscarinic type 1 receptors (TRPC1, TRPC4, TRPC5 heteromers or TRPC4 and TRPC5 homomers); histaminergic type 1 receptors (TRPC3, TRPC6) and purinergic receptors (TRPC7) [32].
It is important to note at this point that Ca2+ release from the SR results in lowering of the Ca2+ content in intracellular stores to a certain degree. This lowering in turn activates a signaling mechanism that allows Ca2+ entry from the extracellular space. This mechanism was originally called [33] store-operated Ca2+ entry (SOCE). Since then, this phenomenon has received much attention, but still the complete mechanism and molecular identity of SOC channels remain unclear [34]. Experiments performed in our laboratory on guinea pig epithelial-free tracheal rings suggest that SOCs are non-selective cation channels that mainly permit Na+ entry causing depolarization (unpublished results). We proposed that such depolarization and increased levels in Na+ induce the NCX to allow Ca2+ influx which in turn activates ClCa, and opening of the Cav1.2 channels [35]. The molecular identity of SOC channels points to the protein ORAI1 as well as to TRPC channels [36, 37]. ORAI1 is a four-transmembrane spanning protein that forms a pore with high selectivity for Ca2+. More recent advances have been made regarding the signaling mechanisms that induce SOC current. The stromal interacting molecule (STIM) 1 has been found to sense Ca2+ concentration within the SR. STIM1 contains an EF-hand Ca2+ binding domain on the N- terminal ER luminal portion. When Ca2+ diminishes in the SR, STIM1 suffers a change in its distribution on the SR membrane and forms discrete clusters called puncta that interact with the plasma membrane. It is now clear that STIM1 couples to Orai1 to refill SR in some cell types. Nevertheless, interaction between STIM1 and other channels such as TRPC has also been observed and could account for SR refilling [38, 39].
NCX is a membrane associated protein that catalyzes electrogenic exchange of 3 Na+ ions and 1 Ca2+ ion across the plasma membrane in a high capacity, and low Ca2+ affinity fashion. This transporter can operate in either the Ca2+ -efflux or Ca2+ -influx mode depending on the electrochemical gradients of the substrate ions. Its physiological relevance became apparent as the role of extracellular Na+ in regulating contraction of smooth muscle was studied. Experiments performed in our laboratory pointed to the NCX as a crucial transporter involved in ASM contraction. In our hands, Na+ substitution by N-Methyl D-glucamine (NMDG) or inhibition of Na+/K+ pump with Ouabain produced an increase in intracellular Ca2 in cultivated ASM cells [40]. Also, Na+ substitution with NMDG or inhibition of Na+/K+ pump with Ouabain increase muscle tension [41], and histamine-pre-contracted guinea-pig tracheal rings show decreased relaxation rate when washed in a Na+ -free solution [42]. The role of NCX in ASM is still unclear, although much evidence has been mounting towards its importance. In further sections of this chapter, various aspects of this transporter will be reviewed in detail.
Similar to SERCA function during SR Ca2+ uptake, the PMCA is constantly extruding Ca2+ outside the cell. The PMCA is a membrane protein that also belongs to the P-type pump family. It operates with high Ca2+ affinity and low transport capacity with a Kd ranging from 10-30 nM at rest to 0.2-0.5 µM at its optimal activation. It is thus considered to be the fine tuner of cytosolic Ca2+ concentration [43]. The PMCA is inhibited by Lanthanum ions and Vanadate, as many other transport systems, and for a long time there was no specific inhibitor available. Recently, some peptides such as caloxin have been synthesized which bind to the extracellular domains of the pump significantly reducing its activity.
The existence of the NCX exchanger was proposed in 1963 [44] as a result of studies in cardiac muscle contraction in low Na+ concentrated solutions. However the proposal was the result of reports from many other investigators who had previously documented the important role that Ca2+ and Na+ played in cardiac contraction. For example, it was reported [45, 46] that cardiac muscle contraction depended on extracellular Ca2+. On the other hand it was [47] described that the force of cardiac contraction increased in the presence of low concentrated sodium solutions and years later other group [48] reported that the increase in the cardiac contraction force was associated with the quotient between the extracellular Ca2+ concentration and the extracellular Na+ concentration. Also, it was reported [44] that the decrease in the extracellular Na+ concentration is related to an increase in the Ca2+ content in cardiac muscle cells. The aforementioned papers and others which will not be mentioned here due to lack of space, lead to the conclusion [44] which says that Na+ and Ca2+ ions had to be transported by a transporter. During the same decade several papers were published, which allowed to suggest the presence of a Na+-Ca2+ transport mechanism in other muscular tissues: skeletal muscle [49, 50], vascular smooth muscle [51] and intestinal muscle [52]. It was not until the end of the sixties when two groups of researchers working separately proposed the existence of a contratransport system coupled for Na+ and Ca2+ [53-58]. Similarly the existence of the Na+-Ca2+ exchanger in the smooth airway muscle was suggested by [59, 60].
The strongest evidence of the existence of the Na+-Ca2+ exchanger was given by the partial purification of the protein [61] and their posterior molecular cloning [62] from cardiac muscle. Other exchangers have been completely or partially cloned in other tissues such as photoreceptors [63], airway smooth muscle [64, 65], brain [66], kidney [67], etc.
We should point out that thanks to the discovery of the Na+-Ca2+ exchanger it was possible to give a rational explanation of the inotropic effect of cardiac glycosides and, also, lead the group of M.P. Blaustein and J. M. Hamlyn to the discovery of the endogenous ouabain [68] a compound that is indistinguishable from plant ouabain, a Na+/K+ ATPase specific blocker.
The mammalian Na+-Ca2+ exchanger belongs to a family of at least 3 genes NCX1, NCX2 and NCX3 which share a high degree of homology at the DNA and protein sequence level. NCX1 is the best characterized and is expressed in most tissues but mainly in heart brain and kidney, whereas NCX2 is expressed mainly in brain and NCX3 in brain and skeletal muscle [62, 69, 70].
An additional member of the mammalian NCX gene family recently identified is the mitochondrial Na+- Ca2+ exchanger (NCLX). This gene is expressed in various tissues, such as pancreas, skeletal muscle and stomach smooth muscle and encodes a 70 KDa protein distinct from the other members of the family. This molecule is localized to the inner mitochondrial membrane and mediates the mitochondrial Ca2+ efflux in exchange for Na+ or Li+, contributing apparently to intracellular Ca2+ homeostasis [71].
NCX 1 is the best characterized at the molecular level and its gene consists of a coding region of 12 exons that encode a protein of 938 amino-acids, and a large upstream regulatory region of more than 2000 bp that contains binding sites for several transcription factors such as GATA 4 SRF, NF-Y, CREB, C/EBP and AP1, among others [72, 73]. The H1 promoter regulates the expression in the heart, K1 in the kidney and Br1 in the brain. The use of each of these promoters in a tissue specific manner produces transcripts with different length of exon 1 and might enable the response to different stimuli. Exon 1 is part of the 5´-untranslated regions (5´-UTR) and each of these alternate exons is spliced to the common coding exon 2. Although this process does not change the coding sequence, it changes the length of the 5´-UTR which might be important for a posttranscriptional regulation.
In cardiac hypertrophy NCX expression is induced by α-adrenergic stimulation mediated in part by p38 MAPK activation and this is dependent on the presence of the proximal CArG promoter. Moreover it seems possible that the activation of the ERK kinase induced by hypertrophic stimuli plays a role in the transcriptional up-regulation of cardiac NCX. Within this region there are at least 3 alternate promoters that confer tissue specificity for NCX expression [73-75].
The major isoform of NCX1 encodes a protein of 120 KDa and NCX2 and NC3 encode proteins of approximately 100 kDa, respectively. The actual topological model suggests five transmembrane helices followed by a large intracellular loop of about 550 amino-acids, flanked by 2 α-repeats, and then the last four transmembrane segments. Spanning the large intracellular loop of NCX1 there is an alternatively spliced region that encompasses 6 exons (A, B, C, D, E, and F), which are expressed in a relatively tissue specific manner. Exons A and B are mutually exclusive and the others are combined with either of these two to produce at least 17 spliced isoforms of the exchanger [69-71]. Exon A appears in excitable tissues (heart, brain, skeletal muscle) and exon B mainly in no-excitable tissues (76-78). The longest spliced isoform is expressed in heart with exon A, C, D, E, F (NCX1.1) and the shortest in brain with the B, D (NCX1.3) isoform. Adjacent to this region there are 2 Ca2+ binding sites, CBD1 and CBD2, and close to the latter there is a alternatively spliced variable region. The interaction between CBD2 and the variable region seems to influence the sensitivity of the NCX isoforms to the regulation by intracellular Na+ and Ca2+ (79).
Other domains in the intracellular loop include an XIP site (eXchanger Inhibitory Peptide), an α-catenin homology region and a putative binding site, within the alternatively spliced region, for the ganglioside GM1. This interaction seems to be specific for exon B expressing isoforms and allow the localization of NCX1 to the nuclear envelope, where might influence not only nuclear Ca2+ but endoplasmic reticulum lumen stores as well, through its vicinity with the nuclear envelope. This interaction has been observed in neuronal and non-neuronal cells, and it has been suggested that the presence of 4 arginine residues in exon B, instead of 1 in exon A could favor a major interaction of the negatively charged ganglioside with these NCX1 isoforms (80).
Apparently NCX may be phosphorylated by protein kinase A (PKA) and protein kinase C (PKC) but it is still unclear whether these posttranslational modifications confer physiological effects directly or indirectly through the interaction with other proteins. It has been reported evidence that the large intracellular loop forms a complex with the PKC and PKA kinases subunits, PP1 and 2 phosphatases, and the PKA-anchoring protein AKAP and although there are compelling evidence for in vitro NCX phosphorylation by PKA and PKC, debate about the functional significance of these findings, still remains. It seems that the intracellular loop is necessary for agonist stimulation of NCX activity, but not necessarily the direct phosphorylation (81-83).
Airway smooth muscle cells and tissue express mainly NCX1, and absence of expression of the NCX2 and NCX3 isoforms. The first molecular evidence of NCX1 expression in ASM was realized in human trachea smooth muscle tissue where the alternatively spliced isoform revealed through reverse transcription coupled polymerase chain reaction (RT-PCR) method was the alternatively spliced isoform NCX1.3 (64).
This same isoform was later found in guinea pig tracheal tissue, showing a high grade homology in the alternatively spliced region among both species, with only minor aminoacid conservative changes. This isoform is predominantly expressed in kidney and contains a 102 amino-acids B exon linked to an 8 aminoacids D exon (84, 65).
At the protein level, NCX1 expression was demonstrated in bovine tracheal smooth muscle, where apparently a 120 kDa and a 110 kDa proteins corresponding to NCX1.1 and NCX1.3 isoforms, respectively, were identified by Western blotting [85]. Functional and comparative studies of the major NCX1.1 and the NCX1.3 isoforms have shown aminoacid differences within these variable exons that influence the inhibitory sensitivity de NCX to intracellular Na+ (77-79).
Recently, an advanced molecular approach based on protein expression knocking down at the messenger RNA (mRNA) level by interference with small RNA molecules (siRNA), has been successfully applied to human airway smooth muscles allowing a better correlation of expression level with function in this tissue. Interestingly, these studies show that histamine and cytokines, like TNFα and IL-13, are able to induce the expression of NCX. When these cells are transfected with siRNA specific for NCX, the protein levels of the exchanger are decreased, as well as the Ca2+ influx elicited by these stimuli [86]. Moreover, in one of these studies it has been shown that cytokine induction of NCX1 is at the transcription level, mediated apparently by a mitogen activated protein kinase (MAPK) and NFκB pathways [87].
In this section, the basic aspects of NCX function will be reviewed considering the molecular mechanics of ion transport, activation of ion transport, interaction between NCX and ionic channels and pharmacology of the NCX.
The mechanism of transport of NCX1 has been widely studied and reveals a consecutive mechanism in which only 1 substrate ion is translocated at a time. Interaction of NCX1 with Na+ or Ca2+ is asymmetric since the apparent affinity for intracellular Ca2+ is several hundred times higher than that for extracellular Ca2+, although affinities for Na+ differ little. Besides being transported substrates, Ca2+ and Na+ regulate the NCX1 activity. In both modes of operation, the NCX1 is activated only when regulatory intracellular Ca2+ binds to a high-affinity site showing K1/2 values of 0.1 to 0.4 µM [88]. In contrast, intracellular Na+ exerts an inhibitory process upon NCX that occurs when the transport sites in NCX1 are fully loaded with Na+ from the cytoplasmic side. This inactivation process is influenced by a variety of factors: it is enhanced at low pH but attenuated by intracellular Ca2+, millimolar ATP or PIP2. The steady-state activity of the NCX1 also exhibits intracellular pH dependence. At pH 6, activity is almost null; whereas at pH 9, activity is maximal [89]. Also, NCX activity shows voltage dependence, attributed mostly to voltage dependence on behalf of the Na+ translocation step, or Na+ binding to the NCX, which is rate limiting in overall reaction [90].
A very interesting effect occurs when alkali metal ions such as Na+, K+ or Li+ are present on the extracellular side: all of them increase NCX activity 2 to 3 times with low affinity. Apart from Na+, these cations bind to sites which are different from the transport sites and are not transported by the NCX [91]. Intracellular metal cations also stimulate the NCX, but apparently they need to be present as well in the internal side of NCX to show such effect. Gadsby et al. [92] found a striking difference between the outward NCX current-voltage relationships obtained in isolated guinea-pig myocytes when extracellular Na+ was completely replaced with Li+ as compared to replacing with NMDG+. This increase in outward current observed when Li+ replaced Na+ suggested that the voltage sensitivity and the magnitude of Na+-Ca2+ exchange depend on the nature of the extracellular monovalent cation present. Our group previously observed that Na+ substitution with Li+ in force experiments performed on guinea pig tracheal rings produced a small reproducible increase in tension (Figure 1. upper trace). Once histamine was added, a further sustained contraction was observed and the peak tension, measured from the previous basal level, showed no significant decrease as compared to control. We suggested that histamine stimulation produces Li+ influx through TRPC, membrane depolarization and activation of CaV1.2 channels. This depolarization is apparently enough to completely explain contraction, as observed when verapamil was added causing almost complete relaxation [35]. It is worth noting that Li+ is not transported through the NCX in either direction [93] and therefore, NCX function under this condition is expected to be null.
Representative traces of isometric force measurements of histamine-stimulated guinea-pig tracheal rings in Na+ -free with LiCl (upper trace), Na+ - free with NMDG+ (middle trace) and PSS (lower trace). PSS = Saline Solution. Force measurements were considered 5 min after histamine stimulation for comparison between contractions.
As mentioned before, the NCX is a transporter whose activity and mode of operation can be finely modulated by the electrochemical gradient for Na+ and Ca2+. It has also been suggested that its localization and physical association with ion channels and cell organelles (as the SR) might determine its modulation [94]. Activation of NCX in the Ca2+ influx mode after agonist stimulation has been observed by different groups. Rosker et al. reported that in HEK 293 cells over-expressing TRPC3 channels, stimulation with carbachol was associated with an increase of intracellular Ca2+ concentration, which depended on extracellular Na+ since its substitution or the NCX inhibition with KB-R7943 reduced such effect. In the same cell line they also reported that NCX and TRPC3 are physically associated after cellular fractionation in low-density sucrose gradients and co-immunoprecipitation. The same group using glutathione S-transferase pull-down technique, which revealed that NCX interacts with the carboxy-terminal of TRPC3, confirmed these data. They also showed by co-immunoprecipitation experiments that NCX and TRPC3 are physically associated [95].
Later, this group tested a similar hypothesis on rat cardiomyocytes, and found that inhibition of the NCX in reverse mode by KB-R7943 also diminished the Ca2+ entry associated with agonist stimulation [96]. Other groups have also observed this functional association using models that better resemble in vivo conditions. It was reported that in rat aortic smooth muscle cells, the NCX inhibitor KB-R7943 as well as the TRPC inhibitor SKF-96365 abolished Ca2+ influx after ATP stimulation. They also observed a similar effect when cells were transfected with a dominant negative transcript for TRPC6 [97].
Hirota et al. [98] have also suggested a functional association between the NCX and TRPC activated by store depletion in dog ASM. In that work, several agonists were tested on tracheal rings together with NCX inhibitor KB-R7943 and sensitivity to this drug was observed. Also, contraction depended on extracellular Na+, corresponding to our own observations. Dai et al. [99] observed in porcine tracheal smooth muscle bundle that Ca2+ waves typically obtained by acetylcholine stimulation were sensitive to TRPC blocker SKF-96365 as well as to KB-R7943. They also observed this sensitivity at the level of muscle contraction, where these drugs, together with nifedipine completely relaxed the muscle.
In our own experience, this relationship between the NCX and TRPC channels became evident in guinea pig ASM. We performed several force experiments on guinea pig tracheal rings and observed that histamine contraction depends on extracellular Na+ and is sensitive to the non-specific NCX blocker KBR-7943 as well as to TRPC non-specific blockers SKF-96365 and 2-APB. These findings have led us to propose that histamine causes Ca2+ entry mediated by the NCX operating in its reverse mode secondary to a cationic influx (primarily Na+) through TRPC. We then proposed that histamine stimulates Na+ influx through TRPC, cell depolarization and the increase in subplasmalemmal Na+ concentration. These conditions might favor first the reverse mode of the NCX and later the activation of CaV1.2 channels which have been characterized in this tissue previously [24]. On the other hand, as Na+ is replaced by NMDG+, neither depolarization nor Na+ influx through TRPC could be possible. Thus Ca2+ release from SR, Ca+2 entries through TRPC and Ca+2 entries through reverse mode NCX would provide for the small histamine-induced contraction observed [35]. Pre-incubation with KB-R7943 allowed us to explore the role of NCX during the beginning of histamine contraction as well as throughout tonic force development. In the presence of KB-R7943 a significant diminishment in maximal force developed as observed, whereas pre-incubation with 70 nM nifedipine had no effect. We thus suggest that NCX is active in its reverse mode at an early stage of contraction after Ca2+ release from the SR, while CaV1.2 channels participate somewhat later during stimulation. In addition, this contraction is also similar to the one observed when Na+ is substituted for NMDG. Our interpretation for this is that when NCX has been inhibited, not only Ca2+ entry is blocked but also membrane depolarization does not reach the threshold for CaV1.2 channel activation.
Ca2+ imaging experiments performed on freshly isolated tracheal smooth muscle cells pointed to the same direction as the tension experiments. We first obtained isolated muscle cells able to contract and to show an increase in FURA-2 fluorescence ratio after histamine stimulation. Stimulation resulted in a peak in fluorescence ratio followed by a plateau of fluorescence just above the basal value (15% of the peak in Ca2+ rise), which persisted until the agonist was washed out. Addition of 100 µM KB-R7943 significantly decreased the change in peak fluorescence ratio in a second stimulation with histamine as well as during the sustained phase (Figure 2.). External Na+ substitution by NMDG+ showed a significant decrease in fluorescence ratio in the sustained phase suggesting that the NCX is operating in the Ca2+ influx mode and that the KB-R7943-insensitive component is due to Ca2+ release from the stores and perhaps Ca2+ entry through TRPC. We also observed that application of SKF-93635 and thus inhibition of TRPC significantly lowers the peak fluorescence ratio and completely abolishes fluorescence in the sustained phase of the curve. This is in agreement with results reported by Dai et al. [99] where SKF-96365 inhibits contraction and Ca2+ waves in porcine tracheal smooth muscle cells.
Representative traces from fluorescence ratio changes observed during stimulation of isolated smooth muscle cells with 10 µM histamine. Cells were stimulated twice with histamine and given a 20 min recovery time between stimulations. Fluorescence ratio was measured as indicated by arrows. During the second stimulation histamine was added together with 100 µM KB-R7943 in PS, A) or 50 µM SKF-96365 in PS, B).
These results led us to propose the following model: Activation of histamine receptors triggers a signaling cascade leading to formation of IP3 and DAG which causes Ca2+ release from SR generating initial contraction. Emptying of the SR by such Ca2+ release, activates TRPC channel opening leading to Na+ influx. This Na+ current in turn causes membrane depolarization as well as a local increase in [Na+]i in the vicinity of NCX which promote its reverse mode of operation. Ca2+ entry mediated by the NCX may add to Ca2+ released from the SR and activate Ca2+-activated Cl- channels [20, 100]. This in turn should cause enough depolarization to activate a larger population of CaV1.2 channels and, together with sensitization events, give rise to a characteristic histamine contraction.
Proposed model that explains the functional interaction between NCX and TRPC during histamine stimulation. Histamine acts on its specific H1 receptor and initiates a signaling cascade leading to formation of IP3. IP3 produces Ca2+ release from SR and this in turn causes TRPC opening. The Na+ current entering through these channels depolarizes the membrane and locally increases [Na+]i in the vicinity of NCX. These conditions would then promote NCX operation in reverse mode as well as CaV1.2 channel activation. Ca2+ entry through NCX might activate Ca2+-dependent Cl- channels and cause even greater depolarization resulting in an activation of a greater CaV1.2 channel population.
Recently, the functional interaction between NCX and the SOCC channel activator STIM1 was observed in human bronchial smooth muscle cells [86]. In this work, electrophysiological recordings of isolated cells revealed an outwardly rectifying current characteristic of the NCX in reverse mode which was completely abolished by KB.R7943. Interestingly, the current was activated by histamine addition and inhibited completely by STIM1 knockdown. STIM is proposed as a sensor of SR emptying which interacts with membrane channels, it is possible that the TRPC channels are activated by STIM1 causing Na+ influx and NCX activation as was previously proposed. This evidence shows again the tight relationship between the NCX and other channels which are activated in response to agonist stimulation or SR emptying.
The NCX working in reverse mode promotes ASM contraction according to the evidence just described. Nevertheless, its mode of operation once agonist is washed seems to be different. In contrast to its alleged role in heart as a fundamental Ca2+ extrusion system [101], we observed that inhibition of the NCX with KB-R7943 during relaxation of guinea pig tracheal rings does not alter the process at all [65]. On the other hand, Na+ substitution by NMDG during washing does retard the relaxation of the rings, indicating that the NCX is turned to the Ca2+ influx mode. This delay in the relaxation process in Na+-free washing was abolished by KB-R943, suggesting the participation of the NCX under these conditions. In accordance with our results, it has also been shown that the NCX plays at most a minor role as a Ca2+ extrusion system during canine ASM relaxation [102]. This is in agreement with our results, suggesting that the NCX found in ASM is active during contraction in the Ca2+ entry mode, but not during relaxation.
Specific inhibitors of the NCX are not yet available for research or therapeutic use. Many divalent and trivalent cations such as La+, Ni2+ and Cd2+, as well as amiloride derivatives or the substituted pyrrolidineethanamine have long been used, although their lack of specificity remain a great handicap for their use. The isothiourea derivative KB-R7943 has been used as a potent inhibitor of the NCX [103]. It is 3-fold less potent on NCX1 and NCX2 than on NCX3 and has a preferential effect on the Ca2+ influx mode of NCX1 [104]. This drug seems to act on specific residues of the NCX1: Val 820, Gln 826 and Gly 833 which lie in a reentrant membrane loop [105]. An important handicap for the use of KB-R7943 is the lack of specificity for NCX, since it has been reported to block ion channels [106], neuronal nicotinic acetylcholine receptor [107], N-methyl-D-aspartate receptor [108] and norepinephrine transporter at relatively low doses. Another more potent and specific inhibitor of NCX is SEA0400. This drug has been reported to be 30 times more powerful than KB-R7943 and to block predominantly NCX1 in CCL39 cells [109,110]. Analysis performed with NCX1 and NCX3 chimeras showed that multiple amino acids are involved in SEA0400 sensitivity encompassing residues 73-108 and 193-230. Regarding its specificity, SEA0400 at 1 µM does not affect CaV1.2 channels, CaV2.2 channels or Na+ channels. The affinity reported for NCX in cultured neurons, astrocytes and microglia has IC50 values from 5 to 33 nM [111]. An important drawback for the use of SEA0400 is that it is not yet commercially available, limiting its use to the general research public. Two other NCX blockers are SN-6 and YM-244769 and are under investigation. The blockers mentioned before have the characteristic that they are poorly active when the exchanger is working in the forward mode under normal conditions (low intracellular Na+) but very active when the exchanger is working in the reverse mode under pathological conditions [112].
As it has been mentioned in previous sections, the NCX plays a critical role in the regulation of intracellular Ca2+ concentration. The direction of Na+ in exchange for Ca2+ depends on the membrane potential and the Na+ and Ca2+ transmembrane ionic gradient. Out of the two types of exchange, the reverse mode (Ca2+ influx mode) has received more attention due to the fact that its function determines extracellular Ca2+ influx into the cell. When this is given in normal conditions is used for either the contraction process or to refill the SR. However, there is experimental evidence that suggests that in certain pathological conditions such as essential hypertension [113], ischemia-reperfusion injury [113] and certain types of cardiac arrhythmia [114] the NCX transports a bigger amount of Ca2+ than necessary.
The usage of NCX blockers such as KB-R7943, SEA0400, and SN-6 [115] have helped to understand the physiological role that the exchanger plays in different tissues. Moreover, they are now seen as potential therapeutic drugs. Indeed, the experimental evidence accumulated over the past few years has allowed to establish that, at least in experimental models, the blockers of the reverse mode of the NCX are useful to diminish the high blood pressure, to abolish cardiac arrhythmias or to reduce the tissue damage after ischemia-reperfusion damage models.
However, as far as we know no reports regarding the use of the NCX blockers have been published in models of airway disease such as Asthma or Chronic Obstructive Pulmonary Disease. It is well known that Asthma is an inflammatory chronic disease characterized by reversible airflow obstruction and nonspecific airway hyperresponsiveness. In spite of the drugs for Asthma treatments available such systemic or local steroids, leukotrienes inhibitors and/or smooth muscle airway relaxants (B2 adrenergic agonist) no absolute control of the disease is obtained. Thus, and because the prevalence of Asthma worldwide has increased in the past few years it challenges the discovery of new and better pharmacological treatments for it. Throughout the past years it has been suggested that the use of NCX blockers could be of some help in the therapeutic management of this disease but the experimental information is scarce. Our group reported [35] that the tonic phase of the contraction induced by histamine is partially blocked by KB-R7943 and its effect is not due to the Ca2+ voltage dependent channel blockage since these had been previously inhibited by Nifedipine. Other groups have reported similar results to ours [116-118]. Therefore, it is expected that in the next years different research groups will proceed to investigate if NCX blockers have any kind of therapeutic use in animal Asthma models.
This work was supported by CONACyT grant No. 62220 and CIHR grant MOP10019.
Today, the greatest success in agriculture will be to achieve the desired increase in production by reducing the negative environmental conditions. This can only be achieved by implementing sustainable methods and sustainable solutions in agriculture. The fact that the agricultural activities and practices are compatible with the environment and being permanent is great importance in terms of contributing to the sustainability of the ecology. There are many definitions and explanations about sustainable agriculture [1]. Sustainable Agriculture includes all of the systems and practices that will improve the protection of the environment and natural agricultural resources necessary to ensure the production of adequate and high quality foodstuffs at affordable costs which the rapidly growing world population needs. To be fully self-sufficient for sustainable agriculture is not a requirement. Long-term stability and efficiency is required. For this purpose, the minimum and most economical and fastest way of implementation of each application in agriculture is one of the priorities that should be focused on the protection of agricultural areas and natural resources.
If an awareness of sustainable practices is to be created, it is necessary to rethink in detail what the concept of agriculture means first. The questions such as: What is agriculture and how should a production be made to meet increasing agricultural demands? Is agriculture only an activity on the field, or is it possible to produce more qualified by applying new production techniques? What methods should be applied to obtain sufficient product without damaging nature? are required to find answers firstly [2].
All of the work done on soil in order to grow the necessary and useful plants and animals for the survival of the people and to obtain the products is called agriculture. In order to meet the growing agricultural needs in a healthy manner, water resources should be protected and soil should be developed and original seeds should be stored and reproduced for the future. At the same time, an increase in soil fertility, protection of water, protection of valuable seeds and biodiversity need to be taken into account.
In general, many methods are applied under the definitions of traditional, organic, industrial, ecological, smart and integrated, and each method differs from the others [3]. Sustainable agriculture mainly focuses on increasing the productivity of the soil and reducing the harmful effects of agricultural practices on climate, soil, water, environment and human health. Reduces the use of non-renewable sources and inputs from petroleum-based products and uses renewable resources to generate production. In general, it focuses on the needs, knowledge, skills and socio-cultural values of the local people.
Some general principles of sustainable agriculture can be listed as follows:
Soil must be protected and developed: Soil is absolutely necessary for good and healthy products. Soil should be enriched with natural fertilizers such as organic and green manure and compost. Natural fertilizers are healthier for soil, plants, water, air and people than chemical fertilizers.
Water and water resources should be protected: As in life, it needs absolute water in agriculture. In arid regions, the best way to protect water is to grow plants that are suitable for the ecology of the region or that only need water during the rainy season. Green manure and mulch are useful in keeping water in soil. The contour barriers protect the water by preventing the water flow. Another method for preserving water is to apply drip irrigation instead of traditional irrigation methods and to make irrigation time planning.
To control pests and diseases naturally: Instead of chemical control, natural or integrated protection management should be applied to balance nature, products, pests, diseases, weeds and soil. In this regard, techniques such as choosing durable varieties, keeping proper distance between plants in planting, determining the timing of agricultural practices correctly, using natural predators and crop rotation are important for the success of the method.
Cultivate different agricultural products: This is called product rotation. According to the characteristics of the products, for 3–6 years rotation or cultivating multiple crops are the methods of preventing diseases and pests. Thus, nutrients are kept in the soil and diversity in agriculture is ensured and healthy food is provided.
Start with small changes first: Most agricultural techniques have been developed over a long period of time. However, new methods may not always be successful. New ideas should first be tried in small areas, and should be applied when it becomes clear and successful.
The world population is growing at a great pace. There are countries with a population expressed in billions of Asian countries, and in Europe and the Americas it is estimated that the population will soon find billions. This will certainly create a serious need for food in the future. One of the main objectives of industrial agriculture is to ensure that everyone has access to basic needs in the present and future years.
Industrial agriculture, on the one hand, uses more chemical input to meet the increasing demand, on the other hand, agricultural and soil resources are polluted by chemical residues and production potential is reduced. In fact, this is a contradiction. At this point, the sustainable farming method protects both the soil and the environment and ensures the production and the long-term agricultural production. In summary, the benefits of sustainable agriculture are as follows:
With sustainable agriculture method, it is possible to produce more than one product in small areas and high efficiency.
An enterprise with sustainability will have a positive impact on the ecosystem. Efficient soils will have a habitat for animals, but will also contribute to agricultural production.
The fertilization of the soil will ensure long-term use and increase of productivity.
In addition to the benefits to agriculture, contributes to the creation of new areas of employment.
As a result of long years of practices and scientific studies, several common sustainable agricultural practices have been put forward in Figure 1.
Common sustainable agricultural practices [4].
It can be defined as a set of methods that include mechanical and biological controls to reduce the use of pesticides and control pest populations [5]. In this method, Variable Rate Application Technologies (VRA) is applied and unlike traditional agriculture, instead of homogeneous input, it is the application of measurement of productivity differences in the field and appropriate input according to the spatial needs resulting from these differences.
CRP is a land conservation program administered by the Farm Service Agency (FSA). In return for a contract with farmers involved in the program, it is an incentive for farmers to make agricultural production that is sensitive to the environment and improves the environmental health and quality [6]. Contracts for land enrolled in CRP are 10–15 years in length. The long-term aim of the program is to restore valuable land cover to help improve water quality, prevent soil erosion and reduce loss of wildlife areas.
In particular, in order to make agriculture in high slope areas, it is the name given to the arrangement of the land in the form of steps and supported by walls. Thus agricultural applications are possible in these areas.
Scouting is the most fundamental act of traveling in crop fields and make observations. The farmer is required to identify how different areas of development change in his land. If there are problems during the growing season, these problems affect the yield at the time of harvest, so the farmer tries to reduce them. If the problems are not noticed or resolved during the growing season, they may limit the yield, thus reducing the revenue generated. Traditional methods include walking in the field and observing plants manually, while methods such as global positioning systems (GPS) and drones (UAVs) help to make a more accurate decision by making fast and reliable measurements with the help of special equipment and precision sensors.
Cover plants (alfalfa, vetch, etc.) can be cultivated during off-season periods when the soil is bare and can be grown between the main plant rows. These products prevent soil erosion, renew soil nutrients, keep weeds under control, and protect soil health by reducing the need for herbicides [5].
It is the process of producing various products in the field one after the other from year to year respectively. Thus, different parts of the soil are utilized with different products, and pests and diseases that are specific to each product are prevented from spreading.
Intensive or traditional agriculture causes physical and chemical degradation of soil, loss of organic matter, reduced biological activity in the soil and consequently a decrease in crop production. On the contrary, the method of sustainable agriculture envisages a sustainable and profitable farming system based on three basic rules, including soil-free agriculture, continuous soil surface covered with plant or plant debris, and crop rotation [7, 8].
Fertilization, which constitutes 10–15% of the costs of agricultural inputs, is critical for increasing product productivity by up to 50%. The application time and method are of great importance in the fertilization process which is applied to soil in order to meet the basic nutrients (nitrogen, phosphorus, potassium etc.) which are not enough in agricultural soils. Data’s such as climate and weather conditions, soil characteristics and product types are important in determining the appropriate fertilization time.
Mechanization tools that reduce labor requirements in agriculture generally use fossil fuels. Nowadays, the use of fossil fuel energies directly or indirectly in agriculture has not been economically profitable for producers. In developing countries, large amounts of fossil fuels are used in agricultural production, in particular fertilizer production and machinery use. It is not possible to carry out modern agricultural production processes without using fuel. However, the use of combined agricultural tools and machinery in one pass and the use of renewable energy sources instead of fossil fuels will reduce both the cost of fuel in agriculture and reduce the carbon emissions and make the agriculture sensitive to the environment.
Effective irrigation is possible by determining the optimum water amount using different parameters such as soil humidity, effective precipitation rate and evapotranspiration and by determining the correct irrigation time with climate, weather forecasts and real-time weather data. In this way, effective and economical irrigation will be provided by protecting the limited water resources and the environmental and agricultural negative effects of leaching, salinity and fungal diseases caused by excess water will be prevented.
Agricultural ponds are important water sources for irrigated areas. These structures collect water from small sources and allow for efficient storage and use of large flow rates when needed and help to regulate water flow.
Sustainable land management includes many components. The multiplicity of components and the different prescriptions are due to the delicate but complex structure of the method and its applications. According to the FESLM: An International Framework for Evaluating Sustainable Land Management definitions by FAO, sustainable land management combines socio-economic principles with environmentally sensitive technologies, policies and activities [9]. In order for sustainable land management to be feasible, five objectives have been identified as Efficiency, Security, Protection, Vitality and Acceptability, and the implementation and findings of the SLM regulation have been identified as the main pillars to be tested and monitored. Each target has its own characteristics and can be explained as follows:
Efficiency: The return obtained from SLM is more than just evaluating with financial gains, it is evaluated to include the benefits that will be obtained from the protective, health and esthetic purposes of land use.
Security: The management models that support the balance between land use and the existing environmental conditions reduce the production risks, whereas only those approaches that emphasize commercial anxiety increase this risk.
Protection: Soil and water resources should be taken under strict protection for future generations. Locally, there may be additional protection priorities, such as the protection of genetic diversity or the need to protect specific plant or animal species.
Vitality: If the applied land uses do not match the local conditions, the use cannot survive.
Acceptability: If the social effects of land use methods are negative, it is inevitable to fail over time. The part directly affected by social and economic impact is not always clear.
Considering this framework, it should be produced safely in the field, established a production model that will protect the natural resources, the model should be economically feasible and socially acceptable. However, it should also be accepted that the system cannot be sustainable with the practices where the agricultural structure is not properly managed and the land is constantly destroyed. This method requires, in principle, to protect and improve soil fertility, to prevent and correct soil degradation and to prevent environmental damage.
In agriculture, healthy nutrition of the plants and increasing the use of fertilizers depends on the application of nutrients at the time of need, with sufficient and correct methods. Correct plant nutrition management is in interaction with many factors. For example, increasing fertilizer usage efficiency depends on reducing the losses of plant nutrients from soil due to leaching, denitrification, evaporation, surface flow. In fertilizer applications not suitable for the technique, the nitrogen is leaching from the soil or away from the gaseous state and the nutrients such as phosphorus and potassium are transformed into non-volatile forms. As a matter of fact, while 50% of the nitrogen applied to the soil is lost in various ways, 90% of the phosphorus cannot be taken by plants [10, 11]. Studies have shown that fertilizer nitrogen use efficiency is very low for wheat, paddy and corn, and nitrogen utilization rate is between 29 and 42% [12]. High nitrogen losses lead to significant environmental problems such as groundwater pollution, lake and river water eutrophication.
On the other hand, soil quality, soil organic matter and nutrient availability also show significant differences between methods such as minimum soil tillage, conventional tillage, conservational tillage and no-till agricultural systems. Totally used soil quality indicators in minimum data sets include total organic carbon, volume weight, aggregate resistance, usable moisture content, pH and EC [13]. Soil water retention capacity, soil water movement in soil, soil compaction and soil temperature also show significant changes depending on the agricultural system. Therefore, soil management has a special place in terms of fertilizer usage efficiency. In this respect, soil management includes more factors such as chemical fertilizers and the use of organic fertilizers (applied fertilizer type, dose, fertilizer application time, method) and irrigation. Fertilizer application methods are extremely important in terms of fertilizer economy. With the method to be applied, the efficiency of the fertilizers is increased and the larger areas can be fertilized with less fertilizer. In the case of slow and controlled conversion of fertilizers into a useful form, the loss of nutrients, especially nitrogen, is prevented and the plant will be used for a longer period of time and increased usage efficiency.
Soil analysis and soil sampling technique are very important in terms of fertilizer usage efficiency. In fact, it is a known fact that the physical and chemical properties of soils are highly variable in agricultural areas. Regionally, even on field level, soil properties show significant differences depending on distance. In fertilization without considering this feature of the land, some parts of the land will be applied more than the need and in some places less fertilizer will be applied. In this case, fertilizer will be deposited or washed in the soil in areas where fertilizer is given, and in areas where less fertilizer is needed, the yield will be low. Increased fertilizer use efficiency and the decrease in nutrient loss are proportional to each other [14]. Therefore, precision farming practices are one of the most important components of sustainable soil fertility and plant nutrition management.
The aim of this course is to evaluate the soil conditions, product characteristics and the variable productivity related to agricultural conditions within the boundaries of agricultural land in variable rate fertilization technologies in precision farming and to determine the time and amount of fertilization. Variable Rate Fertilization Maps used in this direction indicate the variable applications to different geographical coordinates based on the analysis of these conditions. This technology is also effective in deciding the nature of the fertilizer to be used. Different areas within the field can be evaluated separately and variable nutritional needs can be calculated. With the use of advanced technologies, the topographic structure of the field (different slope levels and depressions), the soil color which varies according to the organic matter content and the temporal yield variability in the field are taken into consideration. With the inclusion of land sampling data, all information is classified and analyzed in different databases; accordingly, the need for qualitative and quantitative fertilizers of the field subfields is determined.
The soils under natural vegetation normally support the population of organisms and soil animals in an active biological activity. They live in plant roots and trash, digging and loosening the soil and use it as a nest. The vegetation is normally compressed by exposure to the effects of rain and soil processing and the effects of humans, animals and machinery. A certain proportion of compaction makes it suitable for the growth of plant roots in the soil and increases the ability of plants to retain the water they need to survive. Exposing the soil to compressing and then drying may cause the surfaces to crust. This reduces the water penetration rate and may cause water to flow from the surface and soil erosion.
Larger land resources were needed to supply food to the growing population, and soils were put under intensive use for overproduction. On the other hand, as a result of the pressure of increasing population, the deterioration in the fertile soil resources and the result of the structuralization show the effects of the loss of the area. As a result of the increase in the need for land resources, many countries around the world need to map their land in detail and use the land according to their capabilities. When the sustainability of natural resources is mentioned, first of all, soil erosion and its negative effects on the environment are one of the first issues that come to mind. Under normal conditions, climate, soil, topography and vegetation are the main elements that complement each other. Soil erosion is the result of this interaction. It is clear that the risk of erosion in agricultural areas is high, and if the conservation measures required by sustainable agricultural techniques are not taken, it will be possible to reach irreversible levels. Moreover, our resources, which are already limited by accelerated soil erosion, may be under great threat in the future.
Managing the physical properties of the soil includes the protection of the soil structure necessary for agricultural production, as well as the application of agricultural techniques and processing techniques to increase the long-term efficiency of the soil. Under these conditions, environment-friendly, healthy, economic and quality production conditions will be provided. Soil cultivation is also important for weed control, and this is usually one of the most important reasons for cultivating the soil. However, the introduction of herbicides has resulted in zero or minimum soil tillage techniques that eliminate the need to soil cultivation. Zero and minimum soil tillage techniques protect the soil from the direct impact of rain and wind by leaving crop remains on the surface. Surface residues prevent soil aggregates from being dispersed, transported by water or wind, the infiltration capacity of the soil is preserved, consequently there is no flow on the soil surface and erosion problem decreases. Generally, 56% water and 28% wind erosion are effective in soil degradation types. Among these reasons, agriculture has an important place with 28% (Figure 2) [15].
Types and causes of soil degradation [15].
Intensive and timeless machine operations cause compression on the soil surface, especially in deeper layers and deterioration of the soil structure. Soil compaction is a state of degradation of soil aggregates and reduced pores between aggregates. Reduction of pore density reduces soil aeration, water drainage and water penetration into the deep layers, causing surface flow in rainy conditions. Soil compaction also complicates germination of the seed, limits the growth of plant roots, affects the biodiversity of the soil and causes the surface soil crusting.
Some of the issues to be taken into consideration for the protection of soil physical structure can be listed as follows [15];
Reduce the number and frequency of vehicle traffic, avoid unnecessary operations.
Select suitable machines for the soil properties and the work to be carried out, check the tire pressure to reduce the pressure on the surface and reduce it if necessary.
Agricultural practices that will increase soil organic matter and encourage soil structure, such as soil aeration, water leakage, heat transfer and root growth should be favored.
In grazing systems, grazing intensity and timing should be planned well.
The most important means of ensuring healthy growth of the plant in sustainable agriculture is the sufficient amount of moisture in the root area of the soil during the plant’s growing season. The first source of this moisture is the natural rainfall. In cases where sufficient water cannot be met by rainfall, the water needed should be given by irrigation water. Inadequate or too much soil moisture in the plant root area usually results in a decrease in yield.
The sustainability of water resources is a social, physical, economic and ecological concept. Sustainable water management encompasses the water needs of future generations, drinking and using, irrigation, industrial and recreational water conservation and ecosystem conservation services. In order to ensure sustainability, the following points should be taken into account:
Irrigation system should be continuously controlled, pumps should be operated at optimum performance, water amount should be measured and water distribution evenness should be ensured.
The irrigation time and amount should be planned by determining the plant water requirement and the most effective use of water should be ensured.
Irrigation should be avoided in the middle of day and windy weather, irrigation should be done at night, and if possible drip irrigation method should be used.
The system should be operated at optimum pressure, pipelines should be checked and leaks should be prevented.
In any case, water, water sources and drainage channels should be avoided contamination.
To reduce waterborne erosion; it should be ensured that the water is infiltrated to the soil with the principle of agriculture and irrigation method which is perpendicular to the direction of inclination.
Production planning should be made considering the water quantity and the distance of water resources.
Discharge of untreated farm wastes and wastewater into natural surface waters should be avoided. Measures should be taken to reduce the negative effects of irrigation on the ecosystem.
In addition, drone and sensor technologies can be used to collect necessary data for the development of an effective irrigation methodology. According to this:
Determination of soil water potential with soil moisture sensors,
Thermal images obtained from drones concerning soil and crop moisture content,
Nitrogen deficiency can be measured by multispectral camera,
A variable-rate irrigation program is created in line with weather data and weather forecasts.
Variable rate applications can be done in optimum timing in fields varying in the field in terms of water requirement.
Integrated Pest Management (IPM), as one of the effective methods used in modern agriculture, takes into account all plant protection methods available in the application. IPM implies the integration of appropriate measures that minimize the risks for human health and the environment by preventing the development of pest populations and by ensuring the use of plant protection products and other forms of intervention at economic and ecologically justified and reduced levels.
A well-designed integrated pest management program (IPM) includes three main steps for maximum effectiveness and minimum environmental impact in pest, weed and disease control [16]:
Find: Producers should first identify pests, diseases or weeds. Then, physical, chemical, biological and regulatory compliance options should be decided.
Watch: Reproduction rates are noted after the identification of harmful species. The determination of the effects of the protection methods and the limit threshold where the plant protection products will be used should be determined.
Select: When the density of harmful species reaches the threshold, many protection options are activated. With other protection methods, the use of pesticides that cause the least damage to the environment is the most effective protection method with harmful species. In addition, early harvesting or other physical protection methods can help minimize crop damage. When deciding on the protection method, the existence of useful species should be taken into consideration, and harmful species can be fought with the species which are the enemy of the pests without any application.
IPM for the prevention or suppression of harmful organisms as well as chemical control; crop rotation, use of appropriate breeding techniques (planting dates and densities, protected cultivation, pruning and direct sowing), use of tolerant varieties and certified seed and planting materials, use of balanced fertilization, liming and irrigation/drainage applications and prevention of spread of harmful organisms by hygiene measures (regular cleaning of machinery and equipment), which can be considered as a number of methods are important for sustainable agriculture [16]. Energy-based innovative cultural techniques: leguminous rotations, use of organic wastes as well as farm based by-products, integrated pest management (IPM), pest and disease prediction, biological and cultural pest control, mulching and mechanical weed control, conservational tillage or no-till, mixed sowing and trap crops should be applied within the system [17].
Covered plants provide important contributions to agricultural production at the point of protection of soil, temperature, humidity or light at the desired level, pest and weed control. The reduction of soil cultivation in sustainable agriculture has brought with it the weed problem. Many plants such as clover, vetch, trefoil, oats, rye, sorghum vary widely according to usage and production purpose. For example, cereals are preferred for weed control, and legumes cultivation is preferred for providing nitrogen to the crop plant. The most important point in the cultivation of cover plants is to know the balance between the cost and the benefits of the system.
The system should both reduce the input cost and increase the product efficiency. Apart from its main purpose, cover crops have many other contributions to agriculture and production. The use of these plants allows increasing the amount of organic matter in the soil by protecting plant biomass and vegetative waste in the field. In this way, soil weathering improves, root growth of plants is encouraged and surface water flow decreases and aggregate formation increases. In addition, an increase in the population of living things such as microorganisms and worms, which contribute to the improvement of the nutritional cycle and soil structure, is achieved.
On the other hand, it is possible to reduce soil tillage, increase soil organic matter, benefit from different depths of nutrients, protect soil moisture, increase soil water holding capacity and weed control. For this reason, cover crop and crop rotation in sustainable agriculture is one of the important applications to reduce production inputs and to make economic agriculture.
The management of agricultural areas by traditional methods, the evaluation and processing of soil characteristics using traditional habits alone are not sufficient for the past, present situation and future productivity of the soil. Therefore, an evaluation of the tillage systems where soil tillage is appropriate to the management objectives and the effects on soil functions can be determined precisely. In determining the soil tillage system, the most suitable tillage system should be selected by evaluating the soil structure and quality, not only for the purpose of loosening and aerating the soil and destroying weeds. In order to compare soil management and processing systems, different indicators can be used in soil quality assessments according to soil conditions.
Today, the most important issue of researchers is the question of whether or not food can be produced enough to feed so many people in parallel with the rapidly increasing population. As a matter of fact, while focusing on this issue, it should not only be focused on the subject to feed of human, and should not be overlooked for the healthy and sustainable feeding. In particular, the non-cultivation agricultural system and protective agriculture in general are facing an ecologically and economically large potential for cultivated areas, whose productivity is decreasing day by day and becoming more open to erosion every day. On the other hand, the relationship between fertilizer, pesticide, tillage and crop rotation issues in sustainable systems and their effects on product yield and income should be well established.
According to most of the researches, agricultural production programs will begin to decrease as a result of rapid soil deterioration with the applied agricultural production programs, carbon balance will deteriorate and it will be difficult to obtain a healthy, sufficient and qualitative product in the not too distant future. Therefore, it is now necessary to increase the agricultural production in a way to protect nature and it is inevitable that sustainable agricultural techniques will be applied to reduce soil erosion, salinization, pollution of water resources and other damages. When planning production growth in agriculture, we are faced with the need and the necessity to develop new methods that guarantee natural resources instead of intensive input techniques, which cause irreversible microorganism losses in agricultural areas.
By applying the yield mapping system in agricultural production, it is necessary to determine the changes in the product characteristics in the land and thus the effective and economic planning of the amount of agricultural inputs to be used. In this direction, precision farming and variable rate applications are the most suitable methods to achieve maximum output by using the optimum and limited input. In contrast to traditional agricultural activities, this practice does not apply the amount of input to be applied to the field equal to each point, and applies variable rate according to the input maps created in line with the yield map. This application determines the need of appropriate input considering the specific conditions and the requirements of the land and weather conditions. Data maps are generated with the help of geospatial data, geographic information system (GIS) technologies and software which are acquired by various sensors on the harvesting machines. Drone and satellite technologies facilitate the creation of visuals that provide important information about land, soil and product structure. In this context, high resolution terrain and plant structure visuals, high resolution relief, slope and product maps can be obtained and thus it is possible to create drainage maps, to evaluate the effect of the slope factor in land efficiency and to obtain various data and base map that can be used in farm management.
Nowadays, with the introduction of Industry 4.0 technology, it is possible to reduce the costs of using natural resources at the required level by ensuring the communication of objects in agriculture. Similarly, all the factors necessary for production with smart systems in the farm are analyzed and presented to the manufacturer simultaneously. With the machines that are in contact with each other and working synchronously, a quick decision can be taken, resource wastage is prevented and quality products are produced. With systems equipped with digital sensors, it is aimed to maximize productivity by providing detailed and real-time information such as the type and amount of fertilizer to be given to the regions, weather conditions, plant mineral need, irrigation time, soil condition, estimated harvest time. Workload and cost are reduced with machines that work together and work synchronously. The producer is given the opportunity to manage and observe the whole farm from a tablet or telephone and by reducing the labor force, efficient, fun, high quality and natural production facilities are created.
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