The percentage sequence identity of βLg orthologue protein sequences, the rmsd when aligning the Cα atoms of monomers and the rmsd when aligning the Cα atoms of dimers.
\r\n\tThe aim of this book will be to describe the most common forms of dermatitis putting emphasis on the pathophysiology, clinical appearance and diagnostic of each disease. We also will aim to describe the therapeutic management and new therapeutic approaches of each condition that are currently being studied and are supposed to be used in the near future.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"278931ae110500350d8b64805c70f193",bookSignature:"Dr. Eleni Papakonstantinou",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/7934.jpg",keywords:"Atopic eczema, Interleukin, Topical corticosteroids, Hand eczema, Blisters, Pruritus, Irritant contact dermatitis, Allergic contact dermatitis, Discoid eczema, Sebaceous glands, Inflammatory dermatitis, Facial rash",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 5th 2019",dateEndSecondStepPublish:"March 19th 2019",dateEndThirdStepPublish:"May 18th 2019",dateEndFourthStepPublish:"August 6th 2019",dateEndFifthStepPublish:"October 5th 2019",remainingDaysToSecondStep:"2 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"203520",title:"Dr.",name:"Eleni",middleName:null,surname:"Papakonstantinou",slug:"eleni-papakonstantinou",fullName:"Eleni Papakonstantinou",profilePictureURL:"https://mts.intechopen.com/storage/users/203520/images/system/203520.jpg",biography:"Dr. med. Eleni Papakonstantinou is a Doctor of Medicine graduate and board certified Dermatologist-Venereologist. She studied medicine at the Aristotle University of Thessaloniki, in Greece and she continued with her dermatology specialty in Germany (2012-2017) at the University of Magdeburg and Hannover Medical School, where she completed her dissertation in 2016 with research work on atopic dermatitis in children. During this time she gained wide experience in the whole dermatological field with special focus on the diagnosis and treatment of chronic inflammatory skin diseases and also the prevention and treatment of melanocytic and non-melanocytic skin tumors. Her research interests were beside atopic dermatitis and pruritus also the pathophysiology of blistering dermatoses. In addition to lectures at german and international congresses, she has published several articles in german and international journals and her work has been awarded with various prizes (poster prize of the German Dermatological Society for the project: 'Bullous pemphigoid and comorbidities' (DDG Leipzig 2016), 'Michael Hornstein Memorial Scholarship' (EADV Athens 2016), travel grant (EAACI Vienna 2016). Since 2017, she works as a specialist dermatologist in private practice in Dortmund, in Germany. Parallel she co-administrates an international dermatologic network, Wikiderm International and she writes a dermatology public guide for patients, as she is convinced that evidence-based knowledge has to be shared not only with colleagues but also with patients.",institutionString:"Private Practice, Dermatology and Venereology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:null}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],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. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6550",title:"Cohort Studies in Health Sciences",subtitle:null,isOpenForSubmission:!1,hash:"01df5aba4fff1a84b37a2fdafa809660",slug:"cohort-studies-in-health-sciences",bookSignature:"R. Mauricio Barría",coverURL:"https://cdn.intechopen.com/books/images_new/6550.jpg",editedByType:"Edited by",editors:[{id:"88861",title:"Dr.",name:"R. Mauricio",surname:"Barría",slug:"r.-mauricio-barria",fullName:"R. 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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"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"50508",title:"Structure, Oligomerisation and Interactions of β-Lactoglobulin",doi:"10.5772/62992",slug:"structure-oligomerisation-and-interactions-of-lactoglobulin",body:'\nβ-Lactoglobulin (βLg) is found in the milk of many mammals and, although it is the most abundant protein present in the whey fraction of ruminant milk [1], it is completely absent in human milk. Due to its abundance and relative ease of purification, bovine βLg has served as a model protein for countless biophysical studies of folding, stability and self-association. Although this has created an extensive literature on the nature of βLg, its physiological function is yet to be determined.
\nβLg belongs to the lipocalin family of proteins, most of which have roles that involve ligand-binding [2]. Its ability to bind hydrophobic molecules in vitro has prompted speculation that βLg is involved in the transport of insoluble and/or chemically sensitive molecules between mother and offspring. However, it is necessary to draw the distinction between demonstrating binding in vitro and identifying an endogenous ligand that translates to a physiological role of βLg in vivo.
\nUnderstanding the behaviour of this protein is of particular interest to the dairy industry, given the potential of βLg to affect the processing and manufacture of milk products; for example, βLg aggregation upon heat treatment is known to contribute to the fouling of heat exchangers during the processing of milk [3]. βLg has also been identified as one of the main immunogenic proteins in cow milk and thus contributes to cow milk allergies [4]. It is, therefore, of value to understand this protein’s physicochemical properties and how they may influence the processing, digestion and immunogenicity of ruminant milk and their products.
\n\nThe purpose of this chapter is to review the knowledge that has been gathered for a range of βLg orthologues from various species with regard to structure, oligomerisation and interaction behaviour under predominantly physiological conditions and to consider the current gaps in our knowledge. The thermal denaturation behaviour of βLg, including heat-induced interactions and fibril formation, has been dealt with in detail elsewhere [5].
\nThe first reported atomic level resolution structure of βLg, solved by X-ray crystallography for bovine βLg [6], showed remarkable similarity to retinol-binding protein and led to the classification of βLg as a lipocalin. Lipocalins are a family of proteins that share a similar structure despite great diversity at the sequence level. The conserved lipocalin fold comprises an eight-stranded anti-parallel β-sheet (strands A–H) that is folded back upon itself to enclose an internal cavity, often termed a calyx, together with a three-turn α-helix calyx (cup) handle that lies approximately above strand H (Figure 1) [7]. This fold allows lipocalins to bind a wide range of hydrophobic ligands, with the cavity size and loop scaffold at the cavity entrance determining selectivity. While they were once simply classified as transport proteins, lipocalins are now known to exhibit vast functional diversity, yet most involve some form of ligand binding [2].
\n\nNumerous high-resolution atomic structures now exist for bovine βLg, along with structures of orthologues from sheep, goat and reindeer and the more distantly related pig. Like other lipocalins, bovine βLg is a small protein, in this case of 162 amino acids with a monomeric mass of ~18,300 Da. As shown in a three-dimensional cartoon form in Figure 2, each subunit consists predominantly of an antiparallel β-sheet formed by eight β-strands, A–H, wrapped around to form a flattened calyx [9]. The calyx is flanked on its outer surface by a three-turn alpha helix. The dimer interface, at least for βLg from ruminants, is formed by the ninth β-strand (I) along with the loop connecting strands A and B. The loops at the closed end of the calyx (BC, DE and FG) are quite short, whereas those at the open end (AB, CD, EF and GH) are longer and more flexible [10].
\nTopology diagram showing characteristic features of lipocalin proteins. The eight β-strands A–H form the antiparallel β-barrel. Strand A is kinked (giving rise to strands A1 and A2) and connects the β-sheet comprising strands A1, B, C and D to the β-sheet comprising strands E, F, G, H and A2. The commonly occurring N-terminal 310 helix and the ubiquitous 3-turn α-helix following strand H are shown. Generally, a ninth β-strand follows the 3-turn α-helix and is packed against strand A2. Figure generated by PDBsum [8] using the structure of bovine βLg, PDB ID: 1BSO.
Crystal structure of one monomer of bovine βLg (PDB ID: 1BSO). Eight β-strands (A–H) form the central antiparallel β-sheet calyx. The calyx is flanked on its outer surface by a three-turn α-helix. The ninth β-strand, I, and the AB loop are involved in dimer formation. The polypeptide chain is shown in rainbow colours, beginning in blue at the N-terminus and ending in red at the C-terminus.
Each monomer of βLg contains five cysteine residues. One exists as a free thiol on strand G and is buried beneath the α-helix that lies alongside the β-barrel, whereas the other four form two disulfide bridges. The first (Cys66-Cys160) links the C-terminus to the CD loop, while the second (Cys106-Cys119) links β-strands G and H [11]. The presence and correct arrangement of these disulfide bonds are crucial for the correct folding of βLg. Recombinant expression of this protein in a soluble form in bacteria requires the simultaneous coexpression of a disulfide bond isomerase along with the use of modified Escherichia coli Origami (DE3) cells [12]. These cells, which carry mutations in the thioredoxin reductase and glutathione reductase genes, provide an oxidising environment and, together with the disulfide bond isomerase, allow the proper formation of disulfide bonds in the cytoplasm [13].
\nAt least eleven protein sequence variants of bovine βLg have been described, with A and B the most common variants [14]. Variant B differs from A by two amino acid substitutions: Asp64Gly in the mobile surface loop (CD) and Val118Ala in the hydrophobic core [15]. Crystal structures of both variants A and B at pH 7.1 have allowed observation of the structural consequences of these sequence differences [11]. Only minor differences can be seen in the calyx, while small changes occur in the main chain conformations in the vicinity of the Asp64Gly mutation. The substitution of Val118 for Ala causes changes in the local structure creating a void volume that weakens several hydrophobic interactions. This may be responsible for the slight decrease in thermal stability of variant B relative to variant A [11]. The conformation of the EF loop is slightly different, but this may be due to differences in crystallisation or imprecision in definition due to the high mobility of this loop.
\nCrystal structures of ovine (sheep) [16, 17], caprine (goat) [18, 19] and reindeer βLg [20] indicate that these orthologues share a high degree of structural similarity with bovine βLg, at both the tertiary and quaternary level (Figure 3), with minimal root-mean-square deviations when aligning the C-α atoms of these structures (Table 1). However, there are significant differences between the structures of these orthologues and that of porcine βLg, which in the crystal structure features a completely different quaternary association [21]. This is not unreasonable considering the lower level of sequence identity (63–65%) between porcine βLg and bovine, ovine, caprine and reindeer βLg, where the latter four share sequence identity in pairwise comparisons of 93–99% (Table 1).
\nCrystal structure of caprine βLg (PDB: 4TLJ, pink) overlaid with bovine βLg structures (PDB: 1BSY, 1BSQ, blue), ovine βLg (PDB: 4CK4, green), reindeer βLg (PDB: 1YUP, purple) and porcine βLg (PDB: 1EXS, grey). Monomer A of each structure is superposed to highlight the variation in orientation of the second monomer.
\n | Bovine A | \nBovine B | \nOvine | \nCaprine | \nReindeer | \nPorcine | \n
---|---|---|---|---|---|---|
Bovine A | \n||||||
% sequence identity rmsd monomer rmsd dimer | \n100 - - | \n98.77 0.208 0.221 | \n95.06 0.463 1.023 | \n95.06 0.397 1.400 | \n93.21 0.429 0.569 | \n65.00 1.849 19.36 | \n
Bovine B | \n||||||
% sequence identity rmsd monomer rmsd dimer | \n98.77 0.208 0.221 | \n100 - - | \n96.30 0.409 0.964 | \n96.30 0.386 1.318 | \n94.44 0.394 0.496 | \n63.75 1.792 19.13 | \n
Ovine | \n||||||
% sequence identity rmsd monomer rmsd dimer | \n95.06 0.463 1.023 | \n96.30 0.409 0.964 | \n100 - - | \n99.38 0.324 1.076 | \n93.21 0.310 0.739 | \n62.50 1.920 19.49 | \n
Caprine | \n||||||
% sequence identity rmsd monomer rmsd dimer | \n95.06 0.397 1.400 | \n96.30 0.386 1.318 | \n99.38 0.324 1.076 | \n100 - - | \n93.21 0.404 1.242 | \n62.50 1.398 19.69 | \n
Reindeer | \n||||||
% sequence identity rmsd monomer rmsd dimer | \n93.21 0.429 0.569 | \n94.44 0.394 0.496 | \n93.21 0.310 0.739 | \n93.21 0.404 1.242 | \n100 - - | \n65.00 1.723 19.06 | \n
Porcine | \n||||||
% sequence identity rmsd monomer rmsd dimer | \n65.00 1.849 19.36 | \n63.75 1.792 19.13 | \n62.50 1.920 19.49 | \n62.50 1.398 19.69 | \n65.00 1.723 19.06 | \n100 - - | \n
The percentage sequence identity of βLg orthologue protein sequences, the rmsd when aligning the Cα atoms of monomers and the rmsd when aligning the Cα atoms of dimers.
Source: PDB IDs for structures used for alignment, performed in PyMol: Bovine A: 1BSY, Bovine B: 1BSQ, Ovine: 4CK4, Caprine: 4TLJ, Reindeer: 1YUP and Porcine: 1EXS.
Although there is a high level of structural similarity among the bovine, caprine, ovine and reindeer orthologues, there are subtle differences between them. When dimers are selected for alignment the root-mean-square deviations for the superposition of these structures are higher than when a single monomer is used for the alignment (Table 1). This indicates that while the tertiary fold of these orthologues is similar, there is flexibility in the orientation of the monomers relative to each other (Figure 3), with different crystal forms, including those of bovine βLg, sampling different conformations.
\nThe ultrahigh resolution crystal structures of caprine and ovine βLg [17, 18] make it possible to clearly define features that in lower resolution bovine and reindeer βLg structures are obscured by disorder and conformational promiscuity. These features include the long flexible CD and GH loops, the C-terminal region, and the AB loops at the dimer interface. However, the more mobile regions of bovine and reindeer βLg structure loops are also the more mobile regions of the caprine and ovine βLg structures. The dimer interface in these ruminant βLg structures is formed by the antiparallel association of the I β-strands and electrostatic interactions between Asp33 and Arg40 residues located within the AB loop of each monomer (Figure 4). Hydrogen bonding between the main chain of Ala34 and the side chains of the Asp/Arg pair holds this residue (Ala34) in an unfavourable conformation. The only other residue found in a less favourable region of the Ramachandran plot is the highly conserved Tyr99, which forms part of a γ-turn [22].
\nDimer interface of bovine βLg [PDB ID: 1BEB]. Close-up views of AB-loops and I-strands are shown where inter subunit hydrogen bonds and electrostatic interactions between side chains and main chains can be seen.
Bovine βLg undergoes several conformational changes with pH. Several studies have used nuclear magnetic resonance (NMR) spectroscopy to determine the three-dimensional structure of bovine βLg at pH 2.6 [23–25], where at very low ionic strength the protein becomes monomeric (see the next section for more details on the oligomeric behaviour of βLg). While monomer–dimer exchange makes it difficult to obtain NMR structures at neutral pH [26], this low pH NMR structure can be compared to crystal structures of bovine βLg solved at higher pH values. The structure of this low pH form is very similar to a subunit of the dimer at pH 6.2 [23]. There are slight deviations in the orientation of the loops and of the three-turn helix flanking the calyx, but overall the tertiary fold and, in particular, the hydrophobic cavity are well maintained at low pH.
\nBovine βLg undergoes another reversible pH-induced conformational change, termed the Tanford transition [26, 27], at close to physiological pH that may be of functional significance. This transition involves movement of the EF loop, which is located at the mouth of the calyx. The EF loop is in a closed conformation at pH ~7.1 and below [11] , burying Glu89 as glutamic acid, whereas it adopts an open conformation at pH values above 7, exposing Glu89 as a glutamate. The structures of ovine, caprine and reindeer βLg solved at pH 6.5–7, 6.8 and 6.9, respectively, all show the EF loop in the closed position, in agreement with bovine structures below pH 7. A recent structure of caprine βLg [19] shows an asymmetric dimer with the EF loop of one subunit in the closed position and the other in the open position, suggesting that goat βLg also undergoes the Tanford transition. It is possible that the Tanford transition plays a role in regulating the ligand-binding properties of βLg.
\nThe oligomerisation of βLg has been studied intensively using various techniques including analytical ultracentrifugation, isothermal titration calorimetry and small angle X-ray scattering [18, 28–31]. Utilising both sedimentation velocity and sedimentation equilibrium analytical ultracentrifugation, Mercadante et al. [31] investigated the oligomerisation of bovine βLg over a pH range of 2.5–7.5. Interestingly, at pH 2.5, 3.5, 6.5 and 7.5, the weight-averaged sedimentation coefficient increased with increasing protein concentration, suggesting a monomer–dimer equilibrium. However, at pH 4.5 and 5.5, the weight-averaged sedimentation coefficient stayed the same, consistent with a single species (a dimer) predominating across the concentrations used in the experiment. This suggests that the dimer is more strongly associated at pH 4.5 and 5.5, values which lie near the isoelectric point of the protein, than at pH 2.5, 3.5, 6.5 and 7.5.
\nMercadante et al. [31] went on to characterise the binding energy of dimer formation as a function of ionic strength. They demonstrated that an increase in ionic strength strongly favours formation of the dimer. At low pH, dissociation of the dimer is extremely sensitive to ionic strength. This is due to the fact that at low pH, ionic strength stabilises the dimer by the association of anions near the dimer interface which mitigate charge repulsion of the positively charged subunits. On the other hand, at neutral pH, a relatively low density of cations in the region of the AB and GH loops can also help to stabilise the dimer, but the effect of ionic strength is less pronounced due to the smaller magnitude of the nominal charge on the protein (−9 at pH ~7.5 and +20 at pH ~2.5).
\nA recent paper [32], featuring the use of synchrotron FT-IR techniques to study the dimer–monomer equilibrium at pH ~7 of bovine βLg at high salt and high protein concentrations, reported dimer dissociation constants orders of magnitude greater that the micro molar values reported by a host of others (see Supplementary Table in reference (31). However, inspection of the FT-IR data would support an interpretation that at the higher concentrations aggregation and denaturation of originally dimeric βLg were occurring.
\nImportantly, the study by Mercadante et al. [31] indicates that under physiological conditions bovine βLg self-associates into a dimer with a dissociation constant within the range of the concentrations studied (5–45 μM). Bovine βLg is, therefore, likely to be dimeric at the concentration and pH typically associated with milk (~3 mg mL−1 or ~165 μM and pH 6.5 [33]). A study of caprine βLg suggests a comparable dissociation constant as for bovine βLg under similar conditions [18]. Given the high level of sequence identity between caprine and ovine βLg [17], it is likely that ovine βLg exhibits similar oligomerisation behaviour. The nonruminant equine and porcine βLg orthologues, however, are monomeric at physiological pH [21, 34]. In contrast to bovine βLg, through a domain-swapping mechanism, porcine βLg forms a dimer at low pH [21].
\nThe dimer interface of bovine, caprine, ovine and reindeer βLg orthologues is composed of an intermolecular β-sheet formed between the I-strands of each monomer along with electrostatic interactions and hydrogen bonds between residues located on the AB loops (see Figure 4). Sakurai and Goto [28] investigated the impact of these elements on the monomer–dimer equilibrium of bovine βLg at neutral pH using analytical ultracentrifugation. They engineered mutants that either disrupted the intermolecular β-sheet or the electrostatic interactions between the AB loops. All of the mutants that introduced a proline residue within the I-strand led to dissociation of the dimer, due to disruption of the intermolecular β-sheet. Substitution of the Asp33 or Arg40 residues of the AB loop with oppositely charged residues was also unfavourable for dimer formation, due to the electrostatic repulsion introduced. When these charge mutants were mixed they were able to form heterodimers, suggesting that the electrostatic interactions between these aspartate and arginine residues contribute to stabilisation of the dimer.
\nSome orthologues, however, such as equine βLg, exist as monomers at neutral pH despite the presence of the I-strands and AB loop residues [35]. Sakurai and Goto [28] created another set of bovine βLg mutants in which they substituted the remaining residues at the dimer interface with those found in the monomeric equine and porcine βLg sequences. These sequence-based mutations did not largely affect the association constant, indicating that dimer stabilisation cannot be ascribed simply to the interface residues of bovine βLg that differ in the monomeric βLg variants.
\nIn a similar, but opposite, experiment Kobayashi et al. [36] aimed to convert the monomeric equine βLg to a dimeric form by substituting I-strand and AB loop residues with those found in bovine βLg. That is, Ser34 and Glu35 in the AB loop of equine βLg were replaced with Ala and Gln, and the sequence comprising the I-strand was replaced with the corresponding bovine βLg sequence. Interestingly these mutants did not form a dimer, further suggesting that the difference in oligomerisation behaviour between the bovine and equine orthologues cannot be explained simply by the sequence differences at the dimer interface. They hypothesised that structural differences must exist between equine and bovine βLg that prevent the same interactions occurring at the dimer interface.
\nTo assess this, Ohtomo et al. [35] constructed a chimera named Gyuba, which means cow and horse in Japanese. Gyuba was made by joining the secondary structural elements of bovine βLg with the loops of equine βLg. The chimera was able to form dimers, and its crystal structure showed that it had a very similar dimer interface as seen for bovine βLg (PDB ID: 3KZA). Taken together, these studies suggest that the entire arrangement of the secondary structural elements and loops of βLg, including hydrophobic interactions, hydrogen bonds between I-strands, and electrostatic interactions and hydrogen bonds at the AB loops, is necessary for dimerisation. Further, it is tempting to speculate that protein dynamics may also play a role in dimer formation.
\nDue to its similarity to retinol-binding protein, the ability of βLg to bind retinol was examined by fluorescence spectroscopy [34]. The fact that retinol was able to bind to βLg, and that it could be modelled into the crystal structure of βLg in a similar position as seen bound in retinol-binding protein, led to speculation that the biological function of βLg is to transport vitamin A in milk [6]. However, since then bovine βLg has been shown to be capable of binding a range of small hydrophobic molecules, as demonstrated in various ligand-bound crystal structures. These bound ligands include vitamin D [33, 37], vitamin A [38], cholesterol [33], a range of fatty acids [39–43] and the fatty-acid derivative 12-bromododecanoic acid [9], as well as more diverse molecules including SDS [44] and various anaesthetic drugs [45]. Ligand binding has also been investigated by a variety of other methods, including equilibrium dialysis, affinity chromatography, electron spin resonance spectroscopy, spectrophotometry and perturbation of intrinsic tryptophan fluorescence [33, 46]. Provided that there is a chromophore on the ligand, induced circular dichroism provides, along with X-ray crystallography, the most definitive method for characterising the binding of ligands. These studies have revealed a broad range of ligands that βLg is capable of binding to.
\nLigand-bound crystal structures serve as definitive proof that small hydrophobic ligands are accommodated within the hydrophobic calyx of βLg. Ligand binding, therefore, is dependent on the opening of the EF loop at the mouth of the calyx which, for bovine βLg, occurs near pH 7 as Glu89 becomes deprotonated and is exposed as a glutamate. The pKa of Glu89 in porcine βLg is higher than in bovine βLg (calculated 9.7 compared to observed 7.3 (see reference [11] and references therein to Tanford\'s original work)), and thus porcine βLg is only able to bind fatty acids above pH 8.6 [47]. In ligand-bound structures the density is often quite poor for the extremity of the ligand and can be ambiguous as to which orientation the molecule faces. However, most can be interpreted by taking into account their chemistry, for instance cholesterol and vitamin D were built into their electron density placing their hydroxyl groups facing out of the calyx as opposed to being buried in the centre of the protein [33]. Qin et al. [9] used a fatty acid derivative, 12-bromododecanoic acid, to unequivocally determine the orientation of the ligand in the binding site, with the carboxylate head group lying at the surface of the molecule.
\nThe lining of the hydrophobic cavity is exclusively hydrophobic, except for two lysine residues (Lys60 and Lys69) at the entrance to the calyx. It is generally agreed that there are two main interactions between βLg and fatty acid ligands; one is the hydrophobic interaction between the hydrocarbon tail of the fatty acid and the interior of the hydrophobic calyx, and the other is the electrostatic attraction between the carboxyl group of the fatty acid and the amines of Lys60 and Lys69. The strength of the interaction between βLg and fatty acids generally increases as the length of the hydrocarbon chain increases, due to an increase in van der Waals’ forces. There is, however, an exception to this rule; the eight-carbon caprylic acid has a greater binding affinity than the ten-carbon capric acid [43]. Until recently, there was no satisfactory explanation for this result. Yi and Wambo [48] have used molecular dynamics simulations to accurately compute the binding free energies between βLg and five saturated fatty acids of 8 to 16 carbon atoms. Their results agree well with experimental results; the binding free energy increases with the number of carbon atoms of the fatty acid, with the exception of caprylic acid, which has a higher binding free energy than the 2 carbon longer capric acid. The van der Waals’ forces between the fatty acid tails and the interior of the βLg calyx increase as the chain length increases; however, for caprylic acid the electrostatic interaction between the carboxyl group and the amines of Lys60 and Lys69 is stronger than these van der Waals’ forces which pulls the caprylic acid closer to the top of the barrel. This allows the hydrophobic tail of caprylic acid to fluctuate more easily, increasing the entropy of this complex, resulting in a greater overall binding free energy.
\nA small number of studies suggests there may be a second, lower affinity, external binding site for hydrophobic molecules [37, 49, 50]. The lower affinity of this binding site may explain the difficulty in obtaining crystallographic evidence of this interaction. However, a crystal structure was recently solved of bovine βLg that identifies two molecules of vitamin D3 bound, one bound within the calyx and the second possibly bound at an exosite between the β-barrel and the α-helix that lies alongside the barrel (Figure 5) [37]. The free thiol of βLg (Cys121) is buried beneath this α-helix and methylation of this thiol appears to reduce the affinity for palmitic acid compared to native βLg, whereas the binding of retinol is not affected [49]. A second binding site may explain how βLg is capable of binding such a wide diversity of shapes of ligands, yet more evidence, such as more convincing electron density, is required before the existence of this site can be conclusively proven.
\nA definitive role for βLg is yet to be ascribed, although several predictions have been made. Most suggestions are for a role in molecular transport between mother and offspring, due to its demonstrated ability to bind a range of ligands. However, the specific identity of the ligand being transported is not clear. Fatty acids have been seen bound to βLg isolated from milk under nondenaturing conditions, but are present in quantities reflecting the fatty acid composition of milk [51]. The apparent lack of selectivity makes it less likely that βLg is a specific fatty acid or vitamin transporter. βLg may still be involved in fat metabolism; there is evidence that βLg can stimulate a pregastric lipase, potentially by binding the fatty acid products and thereby reducing their inhibitory effect on the enzyme [52].
\nFront view (A) and top view (B) of the crystal structure of bovine βLg showing two molecules of vitamin D3 (magenta) bound, indicating the locations of the putative primary ligand-binding site within the central hydrophobic calyx and the second proposed exosite between the β-barrel and the α-helix that lies alongside the barrel. (PDB ID: 2GJ5 [37]).
The closest homologue to βLg in humans is glycodelin (pregnancy protein 14). Inter alia, glycodelin has an immunosuppressive activity in the uterus and is involved in protecting products of the reproductive organs from the immune system [53]. Unlike βLg, glycodelin is a glycoprotein, a property essential for its function. It has been hypothesised that βLg may have diverged from glycodelin following a gene duplication event and has since lost all glycodelin-related function [33]. βLg may now exist primarily as an important source of amino acids for the offspring of the animals that produce it. However, the resistance of this protein to proteolysis by pepsin [54] along with the high level of sequence conservation seen among βLg orthologues, including the highly conserved Glu89 within the EF loop, argue against a simple nutritive function.
\nAnother enticing proposal is the notion that βLg may possess antimicrobial activity [55–57]. The intact protein appears to be capable of inhibiting the growth of Staphylococcus aureus, Streptococcus uberis and E. coli bacteria largely responsible for the prevalent and costly disease, bovine mastitis [55]. βLg also appears to augment the antimicrobial activity of lactoferrin, a protein with a known role in the defence against mammary gland infections [56]. Pan et al. [58], however, reported a lack of antimicrobial activity of native βLg, yet this may be due to the use of a commercial preparation of βLg, as compared to the mild, nondenaturing isolation from milk employed in the aforementioned studies. Pellegrini et al. [57] have also described the antimicrobial activity of four peptides derived from βLg following trypsin digestion. This may point to a protective physiological role in new born calves, perhaps in addition to a protective role in the secretory tissue of the mother. Further studies are needed to provide a comprehensive understanding of the relevance of these findings and to address the mechanisms underlying these antimicrobial observations.
\nUpon heating, βLg (both bovine and caprine) associates with casein micelles through formation of a βLg/casein complex [59], with covalent intermolecular disulfide bonds forming above 75 °C [60]. The pH at which the milk is heated is important in determining how much complex is formed as well as the extent of dissociation of casein from the micelles, which is implicated in the heat stability of the milk [59, 60]. Further studies such as these are necessary for understanding how the processing of both bovine and nonbovine milk may affect the properties of milk constituents and how these may then influence the digestion and immunogenicity of ruminant milk and their products.
\nMuch research has been devoted to understanding the functionality of βLg in milk. There remain large gaps in our knowledge of the interactions of proteins in milk under physiological conditions. There is, therefore, a critical need for research into the interactions that occur between βLg and protein components (other than caseins) in milk under physiological/untreated conditions, as this may finally give us insight into the actual physiological role of this protein and to identify factors that distinguish human neonate responses to milk products sourced from different ruminants. In this regard, the structure of bovine βLg with human immunoglobulin fragments is highly significant [61].
\nβLg has served as the focus of an extensive range of studies for well over half a century, creating a wealth of knowledge about this enigmatic protein. We now have a clear view of the native structure of βLg. This small globular protein is characterised by a central β-barrel composed of eight antiparallel β-strands, creating a calyx that is well suited to binding hydrophobic ligands. An α-helix lies alongside the barrel potentially creating a second, lower-affinity, binding site for ligands. A ninth β-strand, along with the loop connecting the A and B strands, forms the dimer interface of ruminant βLg.
\nUnderstanding the structure of βLg has given considerable insight into its behaviour in solution. Under physiological conditions, ruminant βLg orthologues are predominantly dimeric. The dimer interface involves 12 intermolecular hydrogen bonds and 2 ion pairs, interactions that have been shown to be critical for dimer stability. At low pH the protein is positively charged and thus under low-salt conditions it is monomeric. Increasing the ionic strength screens these electrostatic repulsions and stabilises dimer formation.
\nMany questions regarding βLg remain and, in particular, the physiological function of the protein is still a mystery. The proven ability of βLg to bind hydrophobic molecules along with its stability at low pH, and resistance to proteolytic enzymes are strongly suggestive of a role in fatty acid transport between mother and child. Alternatively, these qualities may enable βLg to enhance milk fat metabolism through the promotion of pregastric lipase activity. However, the absence of βLg in other species, most notably human, needs to be remembered when considering the role of βLg.
\nThe physicochemical properties of bovine βLg will, undoubtedly, continue to be investigated. What is required now is a detailed understanding of these properties in closely related orthologues, in order to understand the underlying processes occurring during the processing and digestion of different ruminant milks. There is also a significant need for exploration into the interactions with βLg that are occurring naturally in milk. This may provide the necessary insight into the function of this protein that is of physiological significance to the mother and/or her offspring, and into the functionality of this protein in milk products from different ruminants destined for human consumption.
\nThe human nervous system is an extremely efficient, compact, fast and reliable computing system, yet it weighs substantially less than most of the computers and performs at an incredibly greater capacity.
The nervous system is subdivided, morphologically into two components, the central nervous system (CNS) consisting of the brain and spinal cord and the peripheral nervous system (PNS) comprising of cranial and spinal nerves and ganglia.
Discrete collections of nerve cell bodies in the CNS are known as nuclei while in PNS, these are called ganglia. The nerve cell bodies are of varying sizes and shapes. Ganglia are present in the dorsal root of spinal nerves, the sensory root of the trigeminal nerve (Vth), Facial (VIIth), Glossopharyngeal (IXth), Vagus (Xth) nerves and in the autonomic nervous system [1]. Some of them have independent nomenclature like the “Gasserian ganglion” for the Vth nerve. Thus ganglia can be divided into two types somatic and autonomic (Figure 1). The nerve cell bodies in each of these differ in their size and shape. Somatic ganglia contain small to large pseudounipolar neurons while the autonomic ganglia contain small multipolar neurons.
Differences in sensory and autonomic ganglia (courtesy: Cranial Nerves and Functional Anatomy, 1st ed. p. 12).
Depending on the number of processes, a neuron can be classified into various categories. Unipolar neurons (no dendrites only an axon) are rare in vertebrates, bipolar neurons (possesses an axon and a dendrite) present in olfactory mucosa and the retina and multipolar neurons (single axon and two or more dendrites) present in the central nervous system except the mesencephalic nucleus of the Vth cranial nerve. An additional type of neuron, the pseudounipolar neuron is present in sensory ganglia and the ganglia of Vth, VIIth, IXth and Xth cranial nerves. It divides into a central and peripheral process (Figure 2).
Types of neurons in nervous system.
The neurons in sensory ganglia are at first bipolar, but the two neurites soon unite to form a single process during development. Structurally and electrophysiologically, both these processes show characteristic features of the axon [2]. Small satellite glial cells tightly wrap the cell bodies of the pseudounipolar neurons in the ganglion. The satellite cells that surround the pseudounipolar neuron are continuous with the Schwann cell sheath that surrounds the axon [3]. A distinctive feature of satellite glial cells by which they are distinguished from astrocytes is that they completely surround the individual sensory neuron. The neuron and its surrounding satellite glial cells form a distinct morphological and probably a functional unit [4]. The somatic ganglia of all the mammalian and avian species demonstrate this arrangement [5]. Satellite glial cells have been implicated in neuronal nutrition, homeostasis, and the process of apoptosis. It is known that astrocytes in the central nervous system perform ‘spatial buffering’ (regulation of K+) and it is presumed that SGCs also perform the same function [5]. Removing K+ from the perineuronal environment would reduce neuronal excitation and therefore contribute to the lowering of pain.
Dorsal root ganglia (sensory ganglia) contain the cell bodies of primary afferent neurons that transmit the sensory information from the periphery into the central nervous system (CNS) [6]. Sensory ganglia were located near the entrance of dorsal root into the spinal cord, and are not a part of CNS. Sensory (somatic) ganglia lie outside the blood-brain barrier and are densely vascularized by fenestrated capillaries, making the neurons and SGCs easily accessible to compounds in the circulation, including chemotherapeutic drugs [7]. Chemotherapeutic drugs show greater accumulation in sensory ganglia than in peripheral nerves [8]. Dorsal root ganglia are more sensitive to heat than other nervous tissues [9]. It is known that pulsed radiofrequency can selectively block sensory nerves while minimizing the destruction of motor nerves. Sluijter et al. reported that the placement of a cannula 1–2 cm peripheral to the dorsal root ganglia could result in maximum effect when pulsed radiofrequency was applied on dorsal root ganglia of the spinal cord [10]. Kikuchi et al. [9] classified anatomical positions and variations of dorsal root ganglia into intraspinal (IS), intraforaminal (IF), and extraforaminal (EF) (Figure 3).
Positions of dorsal root ganglia (DRG) were determined by two schematic lines and classified into three types. Line A: aligning the medial borders of L4 and L5 pedicles, Line B: aligning the centers of L4 and L5 pedicles, Intraspinal type (IS): DRG located proximal to line A, Intraforaminal type: DRG located between line A and B, Extraforaminal type: DRG located distal to line B [9].
The segmental nature of the spinal cord is demonstrated by the presence of 31 pairs of spinal nerves, but there is little indication of segmentation in its internal structure. Each dorsal root is broken up into a series of rootlets that are attached to the spinal cord along the corresponding segment. The ventral root arises similarly as a series of rootlets. These rootlets join to form the ventral and dorsal roots. The dorsal and ventral roots traverse the subarachnoid space and pierce the arachnoid and dura mater. At this point, the dura mater becomes continuous with the epineurium. After passing through the epidural space, the roots reach the intervertebral foramina, where the dorsal root ganglia are located on the dorsal root.
Certain authors have put forward their views regarding the classification of the neurons in the dorsal root ganglia based upon their staining properties into two histological types called “large light” and “small dark”, visible under the light microscope. This has been confirmed by recent electron microscopic analysis that indicates [11] the existence of two basic types of DRG neurons usually termed as type A and type B rather than large light and small dark [12]. The neurons in the dorsal root ganglion can also be divided into three types (small, medium and large neurons) based upon the size of their cell bodies. This classification seems to be more appropriate because the size of the neuronal cell bodies determine their function. The large neurons are mainly concerned with the transmission of proprioception and discriminative touch while the medium-sized neurons transmit nerve impulses associated with sensations like light touch, pressure, pain and temperature. However, the small-sized neurons exclusively transmit action potentials related to pain and temperature.
Glial cells are involved in various pathological processes affecting the central nervous system [13]. There is strong evidence that CNS glial cells are involved (microglia and astrocytes) in the induction and maintenance of neuropathic pain [14]. Following injury of a peripheral nerve, satellite glial cells (SGCs) in the dorsal root ganglia undergo changes in cell number, structure and function, similar to those in the CNS [15]. Peripheral nerve transection increases gap junctions and intercellular coupling of SGCs. SGCs also upregulated the production of proinflammatory cytokines such as tumor necrosis factor-α after lumbar facet joint injury [16].
Thus it is well established that glial cells play a critical role in the genesis and persistence of pain [17]. This is particularly true for the sensory ganglia. Though there are far fewer satellite glial cells than astrocytes or Schwann cells, yet because of their unique location in sensory ganglia, SGCs can strongly influence the afferent sensation. They also respond to the nerve injury by upregulating glial fibrillary acidic protein (GFAP) [18]. One of the ways glial cells in the sensory ganglia transmit signals is through intercellular calcium waves (ICWs) via gap junctions and adenosine-5′-triphosphate (ATP) acting on purinergic type 2 (P2) receptors [19]. This signaling has been shown to be bi-directional between SGCs and neurons (Figure 4).
Schematic diagram describing the structural and functional relations between SGCs and neurons in sensory ganglia, and the consequences of peripheral injury.
Older literature suggests that neurons in dorsal root ganglia can be divided into two histological types called “large light (LL)” and “small dark (SD)” on the basis of staining properties under the light microscope [20]. This population overlaps, but still, they show the several physiological, biochemical and functional differences. Small dark neurons transmit the sensation particularly carried by C fibers (non-myelinated, slow conducting) [21]. Whereas Large light transmits the sensation carried via a fiber (myelinated and fast conducting). Many of the small dark neurons contain substance P or calcitonin gene-related peptide, and they are concerned with thermo- and mechanoreception, and many of them are nociceptive. The terminals of Large light neurons are low threshold mechanoreceptors [22]. Neurons in the sensory ganglia have no dendrites and also do not receive synapses but are still endowed with receptors for numerous neurotransmitters. More recently depending upon the electron microscopic appearance neurons in the dorsal root ganglia were divided into Type A and Type B for large light and small dark neurons respectively. Various other electrophysiological classification depending upon conduction velocity, modality and adaptation rate serves to distinguished large number of functional types of sensory neurons, but it is not clear how these are related to the two basic histological types.
There are contradictions among the researchers regarding the classification of dorsal root ganglia neurons into small, medium and large categories.
One of the studies involving chronic constriction injury model of Bennet and Xie [23] that retains the connection with the original receptive field so that hyperalgesia and allodynia can be demonstrated, classify the neurons in DRG into small (23–30 μm), medium (31–40 μm) and large (41–53 μm), based on the optical measurement of the average diameter [23]. These grouping roughly correspond to those giving rise to C, Aδ and Aβ fibers, respectively [21].
More recently sensory neurons in dorsal root ganglia were classified depending upon the immunohistochemical staining such as Nav1.8 expression in sensory neurons isolated from dorsal root ganglia into small (27–31 μm), medium (31–40 μm) and large (40–50 μm) [24]. There are two factors, namely DNA content and transcriptional activity, that are determinants of cell size [25]. Differences in neuronal body size seem to be primarily determined by the transcriptional activity. A positive correlation between the cell body and total RNA synthesis has been demonstrated in frog neurons, indicating that large neurons need higher transcriptional activities to maintain their large size [26]. The neurons transcription rate is, in turn, positively related to the magnitude of interactions between neurons and their targets, which contributes to the regulation of the soma size and metabolic activity [27].
Sensory neurons of the dorsal root ganglia express multiple voltage-gated sodium channels that substantially differ in gating kinetics and pharmacology. Small diameter (less than 25 μm) neurons isolated from the rat DRG express a combination of fast tetrodotoxin-sensitive (TTX-S) and slow TTX-resistant (TTX-R) sodium channels while large diameter neurons (more than 30 μm) predominantly expresses TTX-S Na current [28].
Viral study including adeno-associated viral vectors (AAV) are increasingly used to deliver therapeutic genes to the central nervous system where they promote transgene expression in postmitotic neurons for long periods with little or no toxicity. In adult rat dorsal root ganglia authors investigated the cellular tropism of AAV8 containing green fluorescent protein gene (GFP) after intra-lumbar DRG injection. And after injection, 2% of small DRG neurons (less than 30 μm) were GFP (+) as compared to 32% large (more than 60 μm) DRG neurons [29].
Electron microscopic features of dorsal root a ganglion divides the neurons depending upon their size and the distribution of their organelles (Figure 5). They were further subdivided into six subtypes according to the arrangement and three-dimensional organization of the Nissl bodies and Golgi apparatus in the perikarya. Type A1 cells were large, clear neurons in which Nissl bodies, separated from each other by pale narrow strands of cytoplasm containing small stacks of Golgi saccules and rod-like mitochondria, were evenly distributed throughout the perikaryon. In type A2, the Nissl bodies assumed a similar distribution but were separated by much wider strands of cytoplasm. Type A3, the smallest of the type A category, displayed densely packed Nissl bodies and long stacks of Golgi saccules which formed a perinuclear ring in the midportion of the perikaryon. Type B cells were smaller and showed a concentric zonation of their organelles. In type B1, large Nissl bodies located in an outer cytoplasmic zone were made of long piles of parallel cisternae interrupted by curved Golgi stacks. Type B2 was characterized by a ring-like Golgi apparatus separating the perikaryon in a cortical zone composed mainly of Nissl substance and a juxtanuclear zone containing mitochondria and smooth endoplasmic reticulum. Type C cells were the smallest of the ganglion cells and contained small, poorly demarcated Nissl bodies and a juxtanuclear Golgi apparatus [30].
Nissl’s staining showing the variety of neurons in the dorsal root ganglion. Black arrow represents the large neurons, red arrow represents the surrounding capsule and the asterisk showed the location of centrally placed collection of nerve fibers [33].
Neurotransmitter study involving tachykinin like substance P (SP) and neurokinin A, which are released by the C-type primary afferent terminals of the small DRG neurons, plays important role in spinal nociception. By means of non-radioactive in situ hybridization and whole-cell recording, authors showed that the small rat DRG neurons also express the NK-1 tachykinin receptor. In situ hybridization demonstrated that the positive neurons in rat DRG sections were mainly small with a diameter of less than 25 μm. And the remaining positive neurons were cells with a medium diameter between 26 and 40 μm. No positive large neurons (more than 40 μm) were observed [31].
Depending upon the molecular weight of neurofilaments and their expression in various categories of neurons in dorsal root ganglia, three different neurofilament subunits have been identified, i.e. light (NF-L), middle (NF-M) and high (NF-H). Previous data showed that all the dorsal root ganglia neurons express NF-M and NF-H while only NF-L defines a distinct group of neurons and significantly large-light neurons [32].
Peripherin, a protein formerly called Y, was first identified by two-dimensional gel electrophoresis in the insoluble fraction of cellular extracts from mouse neuroblastoma cell lines [34]. Its presence has been previously established in the rodent peripheral nervous system mostly by biochemical studies; moreover, biochemical characterization following nerve transection also supports its localization in neurons within the peripheral nervous system [35]. This observation leads to coining of the term “Peripherin” to designate this particular protein entity. Peripherin is a 57-kDa-type III neuronal intermediate filament protein, which is capable of either self-assembling or co-assembling with all of the individual neurofilament subunits [36]. In particular, the small cells of the dorsal root ganglia neurons selectively contain peripherin [35] and thus becoming a useful marker to define the small ganglion cell subpopulation. The exact function of the peripherin is still unknown though it has been suggested to be a determinant of the shape and architecture of the peripheral nerve axons and also provides structural integrity to the cells [37]. Peripherin immunolabeling has seen to be an important marker especially for the study of peripheral nerve development and regeneration since this intermediate filament protein is highly over-expressed during axon elongation [38]. Previously this neurofilament were thought to be inert but in fact these are highly dynamic structures with many diverse function such as relaying the signals from the plasma membrane to the nucleus [39], maintaining the position and function of cellular organelles, and also regulating the protein synthesis [40]. This neurofilament is clinically relevant because of their association with the pathogenesis of some major neuronal disorders. Mainly, accumulation of neurofilament protein and peripherin in proximal axons are associated with amyotrophic lateral sclerosis [41] and also seen in other diseases such as Alzheimer’s disease [42]. Peripherin was used to identify the small to medium-sized neurons in the rat dorsal root ganglia in the present study as because these are associated with the transmission of pain from the periphery to the central nervous system. This would give an idea as to the actual number of neurons within the dorsal root ganglia involved in the transmission of pain (Figure 6).
Immunohistochemical stained section with peripherin antibody of dorsal root ganglion representing the specific staining in small to medium sized neurons (white arrows). Larger neurons (black arrows) [33].
Sensory neurons in the dorsal root ganglia are ensheathed by specialized glial cells termed ‘satellite glial cells’ (SGCs). Recently, there has been considerable interest in these cells as they are profoundly altered by peripheral injuries used to study pain behavior and appear to contribute to chronic pain [43]. Satellite glial cells are the peripheral glial cells, but share many properties with astrocytes in the central nervous system (CNS), including the expression of glutamine synthetase and transporters of amino acids neurotransmitters. However, satellite glial cells differ in some respects from astrocytes, particularly by the tight sheath they make around the neuronal cell bodies [44]. In the dorsal root ganglion, Schwann cells and the satellite cells are activated in response to ischemia, traumatic injury and inflammation [45]. Application of various cytokines to the exposed Dorsal root ganglia resulted in an increase in the discharge rate as well as increased mechanosensitivity of DRG and peripheral receptive fields [46]. Satellite glial cells are the consistent component of the DRG in all the species, yet their contribution to the basic neuronal function remains unknown, although these satellite cells were implicated in neuronal nutrition, homeostasis and the process of apoptosis [5].
Recent studies have demonstrated that a specific glial cell population, the satellite glial cells, has the ability to regulate ion concentration [47] and possess mechanisms for the release of cytokines [48], ATP [19] and other chemical messengers like calcium. Satellite glial cells influence neuronal excitability via the gap junctions [49]. The satellite glial cells undergo major changes as a result of injury to peripheral nerves and appear to contribute to chronic pain [4]. Quantitative studies on several species showed that a number of satellite glial cells per neuron increases in proportion to the neuron’s volume, consistent with the idea that these satellite glial cells support the neurons metabolically [50].
During pathological conditions, such as nerve injury or inflammation, SGCs demonstrate an altered phenotype similar to that seen in activated astrocytes, which includes increased expression of the glial fibrillary acidic protein (GFAP) and synthesis of cytokines [51]. SGCs are therefore said to undergo activation due to injury. Increased coupling by gap junctions between SGCs has been observed in several inflammatory pain and axotomy models [52].
Satellite glial cells (SGCs) in sensory ganglia wraps completely around the neuron. Several investigators claimed that SGCs bear processes and are therefore structurally similar to astrocytes but recent researches are that SGCs are laminar and have no true processes. In general, each sensory neuron has its own SGCs sheath, which usually consists of several SGCs, and thus the neuron and its surrounding satellite glial cells form a distinct morphological and probably functional unit. The region containing connective tissue separates these units. In some cases (5.6% in rat DRG) neurons from a small group containing two to three cells that are enclosed in common connective tissue space [44]. The neurons in the clusters are in most cases separated from each other by SGC sheath. The SGCs envelope usually consists of flat processes that lie close to the neuronal plasma membrane. The distance between the glial cell and neuronal plasma membrane is about 20 nm [44]. The neurons send numerous fine processes (microvilli), some of which fit into the invaginations of SGCs thus increasing the neuronal surface area and may allow an extensive exchange of chemicals between two cell types. A study on cultured SGCs of embryonic and neonatal rats showed that SGCs could transform into astrocytes, Schwann cells and oligodendrocytes [53].
Quantitative studies on several species showed that the number of SGCs per neuron increases in proportion to the neuron volume [50] consistent with the idea that SGCs support the neurons metabolically. It was also found that the mean volume of the nerve cell body corresponding to an SGC was lower for small neurons than for large neurons, which implies that the metabolic needs of small neurons are better satisfied than those of large ones. Therefore, smaller neurons have a higher resistance to insults, which seems to be the case for mercury poisoning. However, there is experimental evidence that smaller neurons are more likely to die following axonal damage [54]. As sensory ganglia are not protected from substances circulating in the blood, SGCs may be important in the context of exposure to toxic substances. In several studies, SGCs were examined after poisoning with heavy metals and it was found that these cells take up organic mercury compounds [55], and lead [56]. Mercury poisoning also caused SGCs proliferation [57]. Nineteen days after the administration of organic mercury to rats, SGCs in DRG were heavily labeled for mercury, and their ability to take up GABA was greatly diminished. Interestingly, small neurons were considerably less labeled for mercury than large neurons, which could be attributed to a more effective protection by SGCs. Prolonged (3–18 months) administration of lead acetate to rats resulted in prominent changes in SGCs in DRG, which included proliferation and hypertrophy of these cells. Although a certain degree of neuronal damage was observed, it can be proposed that the changes in SGCs provide a better protection to the neurons during lead poisoning.
The satellite glial cells neighboring the pseudounipolar neurons have a highly negative resting membrane potential and noticeable potassium permeability. The primary means of limiting extracellular levels of potassium in the sensory ganglia occurs through the process commonly called spatial buffering or syphoning which is mediated by satellite glial cells. The maintenance of a low extracellular potassium concentration is crucial for controlling the neuronal resting membrane potential and neuronal excitability. In sensory ganglia increased neuronal excitability has been associated with the occurrence of altered sensation, including the development of the neuropathic pain [58]. In the CNS buffering of extracellular potassium ions is carried by astrocytes, which consist of uptake by inwardly rectifying potassium (Kir) channels and dissipation through other channels and gap junctions [59]. It is established that the Kir current and Kir4.1 expression occur in the satellite glial cells [60]. Voltage-gated potassium channels are one of the important physiological regulators of the membrane potentials in excitable cells including sensory ganglion neurons.
Central nervous system glial cells are increasingly known to be important regulator of synaptic activity and the key functional unit of nervous system [61]. Even though many of the same voltage-sensitive ion channels and neurotransmitter receptors of neurons are found in glia; glial cells lack the membrane properties obligatory to fire action potentials. Nevertheless, these ion channels and electrogenic membrane transporters permit glia to sense indirectly the level of neuronal activity by monitoring activity-dependent changes in the chemical surroundings shared by these two cell types. Complex imaging methods, which allow observation of changes in intracellular and extracellular signaling molecules in real time, show that glia, communicate with one another and with neurons primarily through chemical signals rather than electrical signals. Many of these signaling systems overlap with the neurotransmitter signaling systems of neurons, but some are specialized for glial-glial and neuron-glial communication. Neuron-glia cell interaction through gap junctions and extracellular paracrine/autocrine processes are believed to be important in the development of peripheral sensitization within the trigeminal ganglia [62]. Peripheral sensitization, which is characterized by increased neuronal excitability and a lowered threshold for activation, may possibly trigger a migraine attack. Moreover, activation and sensitization of the trigeminovascular afferent fibers appear crucial for initiation of migraine pain and for subsequent central centralization, in which increased excitability of second-order neurons leads to pain and allodynia. Increased gap junction communication between neurons and satellite glial cells was observed in the trigeminal ganglion in response to chemical activation of sensory trigeminal nerves [62].
Increased neuronal-glial signaling by way of gap junctions is common in neuroinflammatory CNS disorders, such as cerebral ischemia and Alzheimer’s disease and may have underlying pathological significance [63]. Tonabersat (SB-220453), a compound that binds selectively and with high affinity to a unique stereoselective site i.e. the gap junctions and inhibits it in rats and human brains [64]. After an injury, the numbers of gap junctions that connect satellite glial cells increases [43] in a probable adjust to the greater release of potassium ions with intense neuronal activity. Injury to a peripheral nerve does not directly impact satellite glial cells integrity. However, changes in injured neurons can influence the ability of the surrounding SGCs to regulate K+ via neuromodulators such as adenosine triphosphate (ATP) and nitric oxide (NO) [65].
Satellite glial cells have unique proteins that include the inwardly rectifying K+ channel Kir4.1 [43], the connexin-43 (Cx43) subunit of gap junctions the purinergic receptor P2Y4 [66] and soluble guanylate cyclase. There is also evidence of the presence of small-conductance Ca2+−activated K+ channel SK3 that is present only in satellite glial cells. All the above proteins are involved, either directly or indirectly, in potassium ion (K+) buffering and, thus, can influence the level of neuronal excitability, which, in turn, has been associated with neuropathic pain conditions (Figure 7). They also used in vivo RNA interference to reduce the expression of Cx43 (present only in SGCs) in the rat trigeminal ganglion and showed that this resulted in the development of spontaneous pain behavior. The pain behavior is present only when Cx43 is reduced and returns to normal when Cx43 concentrations are restored [66, 67].
Satellite glial cells involved in maintenance of potassium homeostasis [66].
Glial fibrillary acidic protein is principle intermediate filament in mature astrocytes of the central nervous system and satellite glial cells of sensory ganglia [4]. GFAP is strongly unregulated in response to CNS damage [68]. It is thought to be important in astrocyte neuronal interactions, astrocyte mobility and shape and for maintenance of homeostasis and vascular permeability at the blood-tissue interface [69]. GFAP is essential for normal white matter architecture and blood-brain barrier integrity and its absence leads to late-onset CNS dysmyelination [70]. Increased GFAP expression occurs in activated glial cells. Activated astrocytes are characterized by hypertrophy, the release of pro-inflammatory cytokines (IL-1, IL-6 and TNF-a), the release of nitric oxide and prostaglandins, and up-regulation of the intermediate filaments GFAP and vimentin [17]. Likewise, satellite glial cells (SGCs) display increased expression of GFAP after neuronal injury or inflammation and undergo a number of changes similar to those seen in astrocytes, such as synthesis of cytokines [71]. GFAP expression increases in the satellite glial cells of trigeminal ganglia after tooth pulp injury [72]. The present study also investigated the expression of GFAP in the satellite glial cells following acute pain (Figure 8).
Immunohistochemical staining for the section of DRG using GFAP antibody. Black arrows representing the location of satellite glial cells. Red arrow showing the communication between two neurons [33].
GFAP is a marker of activated satellite glial cells and astrocytes [48]. These ropes like filaments are called intermediate filaments because their diameter of 8–10 nm is between those of actin filaments and microtubules. Nearly all-intermediate filaments consist of subunits with a molecular weight of about 50 kDa. Some evidence suggests that many of the stable structural proteins in intermediate filaments evolved from highly conserved enzymes, with only minor genetic modification. Intermediate filaments are formed from nonpolar and highly variable intermediate filament subunits. Unlike those of microfilaments and microtubules, the protein subunits of intermediate filaments show considerable diversity and tissue specificity. In addition, they do not possess enzymatic activity and form nonpolar filaments. Intermediate filaments also do not typically disappear and reform in the continuous manner characteristic of most microtubules and actin filaments. For these reasons, intermediate filaments are believed to play a primarily structural role within the cell and to compose the cytoplasmic link of a tissue-wide continuum of cytoplasmic, nuclear, and extracellular filaments. A highly variable central rod-shaped domain with strictly conserved globular domains at either end characterizes intermediate filament proteins. Although the various classes of intermediate filaments differ in the amino acid sequence of the rod-shaped domain and show some variation in molecular weight, they all share a homologous region that is important in filament self-assembly. Intermediate filaments are assembled from a pair of helical monomers that twist around each other to form coiled-coil dimers. Then, two coiled-coil dimers twist around each other in antiparallel fashion (parallel but pointing in opposite directions) to generate a staggered tetramer of two coiled-coil dimers, thus forming the nonpolarized unit of the intermediate filaments. Each tetramer, acting as an individual unit, is aligned along the axis of the filament. The ends of the tetramers are bound together to form the free ends of the filament. This assembly process provides a stable, staggered, helical array in which filaments are packed together and additionally stabilized by lateral binding interactions between adjacent tetramers [2].
Total six classes of intermediate filament are present in body, e.g., Class II and I include keratin and cytokeratin and class III include vimentin, glial acidic fibrillary protein (GFAP) and peripherin.
GFAP is the principal intermediate filament in mature astrocytes. GFAP is a soluble protein isolated from the multiple sclerosis plaques and presumably arising from the glial filaments [73]. The GFAP gene is located on the long (q) arm of chromosome 17 at position 21. Mutation in the GFAP results in Alexander disease characterized by rare leukoencephalopathy affecting predominantly the brainstem and cervical cord with insidious onset of clinical features and unified by the presence in astrocytes of Rosenthal fibers (protein aggregates mainly contain glial fibrillary acidic protein (GFAP) and small stress proteins) in the astrocytes especially in the subpial and subependymal in location. It is strongly upregulated in response to the CNS damage [68]. It is thought to be important in astrocyte-neuronal communication and is believed to modulate astrocyte motility and shape. Satellite glial cells (SGCs) responsible for the maintenance of homeostasis and vascular permeability at the blood-tissue interface [69]. In the peripheral nervous system, neurons located in sensory ganglia are tightly surrounded by SGCs, following injury these cells undergo modification in structure and function [15]. According to Feng et al., after ligation of the L5 spinal nerve, mechanical allodynia developed in the ipsilateral hind paw and expression of GFAP in the ipsilateral DRG increased significantly as early as 4 hours after surgery, and gradually increases up to peak level at day 7 and then stayed at high level till day 56 [74]. Significant change seen among the sizes of neurons means small to medium size neurons shows maximum GFAP immunoreactivity at 12 hours and on day 7, a number of larger neurons was surrounded by GFAP stained satellite cells.
Gap junctions, tight junctions, adherens junctions, desmosomes, hemidesmosomes, focal adhesions, chemical synapses, and immunological synapses are complex multiunit plasma membrane structures that assemble in a localized spatial and temporal organization to maintain structural tissue organization and to provide the cell signaling functions. At least nine connexins (Cx26, Cx32, Cx33, Cx36, Cx37, Cx40, Cx43, Cx45, Cx46) are expressed to various degrees in the nervous system. Functional studies in diverse cell types and in various exogenous expression systems have revealed that gap junction channels formed by different connexins are regulated differently, both at the single channel level (gating controls such as voltage sensitivity and variations in unitary conductance) and at the level of synthesis (expression, altered for example by hormones, extracellular matrix). Some gap junction channels are more sensitive to various gating stimuli than others, some display some degree of ionic selectivity, and some will pair promiscuously with other connexins (heterologous channels) while others are quite selective in their interaction (homologous channels). Such differences are important from the standpoint of the physiological roles of gap junctions in different cell types, as well as in the establishment of communication compartments within the nervous system [75]. Connexins are differentially expressed in the brain during ontogeny. Most recently, tissue culture preparations from embryonic neural tissue have allowed manipulation of individual cells and evaluation of changes in junctional distribution and expression during maturation. Such studies have clarified the relationships between sequential changes in phenotypes of neural cells, with the extent of coupling mediated by Cx43 (which is abundant in neural precursor populations) and the appearance of other gap junction proteins. Expression pattern of Cx32, Cx43 and Cx30 during the development in rat brain indicates the Connexin-43 appears first at embryonic days 12-18 [76] and that Cx32 protein and mRNA appear during first or second postnatal week and increases during development. Immunohistochemical analysis of postnatal rat brain has shown that Cx43 first appears along radial glial cells and is most intense along cerebellar Bergmann glial cells [77]. Glia represents the major cell population in the CNS coupled by gap junctions. Indeed, compared to neurons, the level of connexin expression is high in these cells and persists until the adult stage [75]. For the two main types of macroglial cells, the astrocytes and the oligodendrocytes, several connexins have been detected [78]. Gap junctional communication is not limited to either astrocyte-to-astrocyte or oligodendrocyte-to-oligodendrocyte, but it also occurs in between both cell types. In the adult brains, the predominant connexin is Cx43, which is abundant in astrocytes and is also expressed in leptomeninges, endothelial cells and ependyma. The second type of microglia, the oligodendrocytes (and their peripheral counterparts, the Schwann cells), appear to express a different gap junction protein, Cx32, although to a lower extent in situ than the level of Cx43 expression exhibited by astrocytes. Astrocytes express Cx43 and are well coupled in vivo and under culture conditions. However, the strength of coupling and degree of Cx43 expression between astrocytes varies depending on brain regions being higher in the hypothalamus than in the striatum. Although glial gap junctions do not generate action potentials in normal conditions and are devoid of synaptic contacts, connexin channels provide a route that allows changes in membrane potential to be transmitted from one cell to its neighbors. Recently, the participation of astrocytic gap junction in neuroprotection has been investigated by comparing neuronal vulnerability in the presence of either communicating or non-communicating astrocytes [75].
Gap junctions and their consistent connexin proteins have represented a new challenge in all tissues where they occur but no structure is more complex or more interconnected than the mammalian central and peripheral nervous systems (CNS and PNS). The term “Gap junctions” arose from the work of Revel and Karnovsky, who described the fine structure of the interconnections between mouse cardiomyocytes and between hepatocytes. Later development of specific antibodies to gap junction proteins and eventually the cloning of these connexin molecules have now led to the availability of a variety of techniques by which the distribution and expression patterns of specific types of gap junctions have been defined in a varied number of tissues, including the brain. Gap junctions are the clusters of intercellular channels that are composed of 12 subunits, 6 of which form a connexion or hemichannel contributed by each of the coupled cells [79]. Gap junctions are permeant to molecules up to 1 kDa and are found in virtually all cell types in mammals; few exceptions include circulating erythrocytes, spermatozoids and adult innervated skeletal muscle cells [80]. Gap junctional communication is essential for many physiological events, including cell synchronization, differentiation, cell growth, and metabolic coordination of avascular organ including epidermis and lens [81]. Connexin family members share a similar structural topology. Each connexin has four transmembrane domains that constitute the wall/pore of the channels. These domains are linked by two extracellular loops that play roles in the cell-cell recognition and docking processes. There are three unchanged cysteine residues in each loop, which solely form intraconnexin disulfide bonds [82]. The transmembrane domains and extracellular loops are highly conserved among the family members. Furthermore, connexin proteins have cytoplasmic N- and C-terminal and a cytoplasm loop linking the second and third transmembrane domains. Although the N-terminus is conserved, the cytoplasmic loop and C-terminus show great variation in terms of sequence and length. The cytoplasmic tail and loop are susceptible to various post-translational modifications (e.g., phosphorylation), which are believed to have regulatory roles [83]. Connexons (hemichannels) are then carried to the cell surface via vesicles transported through microtubules, which fuse to the plasma membrane. These hemichannels can either form nonjunctional channels in unopposed areas of the cell membrane or diffuse freely to regions of cell-to-cell contact to find a partner connexon from a neighboring cell to complete the formation of intercellular channels. Intercellular channels then cluster into gap junction plaques, a highly dynamic event involving removal of old channels from the center of the plaque, while adding new gap junction subunits to the periphery [84]. The intercellular channels from the middle of the plaque are internalized into vesicular structures called “annular junctions” [85], which either fuse with the lysosome for degradation by lysosomal enzymes or are targeted to the proteasomal pathway [86]. The continuous synthesis and degradation of connexins through these mechanisms may provide for the quick adaptation of tissues to changing environmental conditions. Unopposed hemichannels can also be functional under certain conditions, including mechanical and ischemic stress. Under these circumstances, open hemichannels are thought to facilitate the release of a variety of factors such as ATP, glutamate, and NAD+ into the extracellular space, generating different physiological responses [87].
Up to date, there were 20 proposed members of the connexin family of proteins that form gap junctional intercellular communication channels in mammalian tissues, and over half are reported to be present in the nervous system. Identification of the several connexin proteins at gap junctions between each neuronal and glial cell type is necessary for the sensible design of investigations into the functions of gap junctions between glial cells and into the functional contributions of electrical and “mixed” (chemical plus electrical) synapses to communication between neurons in the mammalian nervous system (Figure 9).
Immunohistochemical staining using connexin-43 antibody. Black arrows represent the location of gap junctions between the satellite glial cells and the neuronal bodies [33].
Gap junction’s role has been well evaluated concerning cell-to-cell interaction. There are two effects derived from gap junction’s function that may determine life and death of the connected cells [89]. The bystander effect promotes the death of normal cells adjacent to an apoptotic cell by diffusing toxic metabolites through gap junctions. In the same way there is the Good Samaritan effect that allows a condemned cell to live by draining the toxic metabolites to adjacent cells and maintaining cells integrity and thus tissue homeostasis. In this way gap junctions perform a dual function either saving or killing interconnected cells [88]. Some pathological conditions are directly related to gap junctions or to their altered function. Some human diseases are caused by mutated connexins [89]. Mutations on Cx32 induce a peripheral neuropathy named Charcot-Marie-Tooth disease. The many conductivity changes observed in this disease may be caused by altered protein traffic to the junctions, altered channel permeability and, sometimes, altered conformation of heterotypic channels [78]. Mutations of Cx36 may lead to the most common hereditary non-syndromic deafness. Cx43 structure may be altered in some forms of human epilepsy where Cx43 mRNA expression may or may not be altered. High Cx43 levels have been detected in β-4 positive amyloid plaques of Alzheimer’s disease [77], indicating either astrocytes invasion of the plaques or increased Cx43 expression by astrocytes, as observed in PC12 cells (cells from a rat pheochromocytoma) with increased expression of carboxy-terminal portions of amyloid precursor protein [90]. However a higher Cx43 expression in that area may reflect the existence of many activated macrophages/microglia. The decrease of Cx43 within an inflammatory focus suggests that factors as IL-1 β are involved in astrocytic connectivity decrease as observed in autoimmune experimental encephalitis.
IntechOpen publishes different types of publications
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