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Muscarinic acetylcholine receptors (mAChRs) are widely expressed in both the central nervous system and peripheral nervous system and play a crucial role in modulating cellular activity and function. While these receptors have been extensively studied in mammals, their presence and role in avian species remain a relatively unexplored area of research. Nonetheless, several studies have suggested the existence of multiple functional muscarinic receptors in various avian species, including the vestibular periphery of pigeons, retinal cells, intestinal smooth muscles, dorsal root ganglia, developing hearts in chickens, and avian salt glands. Despite this, only the M2-M5 subtypes have been characterized, except for some studies that suggest the existence of functional M1 receptors in avian species, such as in the dorsal root ganglia, retina, heart, and vestibular periphery. In this paper, we review the distribution of avian muscarinic receptor subtypes, the characterization of muscarinic acetylcholine receptors in various organs and organ systems, and the sequence similarity of mAChR 2 and mAChR 3 between various birds and animals. Given the current gaps in our understanding, more research is needed to investigate further the function and expression of mAChRs in avian species.
Department of Veterinary Pharmacology and Toxicology, College of Veterinary and Animal Sciences, Thrissur, India
Suresh Narayanan Nair*
Department of Veterinary Pharmacology and Toxicology, College of Veterinary and Animal Sciences, Thrissur, India
Basavapura Mahadevappa Sanjay
Safety Assessment, Syngene International Ltd, Bengaluru, India
Sanis Juliet
Department of Veterinary Pharmacology and Toxicology, College of Veterinary and Animal Sciences, Wayanad, India
*Address all correspondence to: suresh@kvasu.ac.in;, snn11@rediffmail.com
1. Introduction
It is well established that mammals have got multiple functional receptors for neurotransmitters, and their role in the physiology of lower vertebrates is still less explored. Neurotransmitters are signal molecules with a confirmed neuronal release [1]. Among the different types of neurotransmitters, the major neurotransmitter released is acetylcholine (ACh) [2]. There are two types of acetylcholine receptors (AChRs) which are the nicotinic acetylcholine receptors (nAChRs) and the muscarinic acetylcholine receptors (mAChRs). Of these, the muscarinic receptors, are membrane proteins that belong to the superfamily of G-protein coupled receptors (GPCRs) that transmit their signals into the cell through heterotrimeric GTP-binding proteins (G-proteins), having seven transmembrane domains [3]. mAChRs are the most predominant cholinergic receptors in the central and peripheral nervous systems which plays an important role in modulating cell activity and function [4].
Moreover, muscarinic receptors are present in virtually all organs with a predominance of individual subtypes in various tissues and organs [5]. There are five genetically distinct subtypes of mammalian mAChRs (M1-M5) [6] in neurons and other cell types. M1, M4, and M5 receptors are most abundant in the central nervous system (CNS), while M2 and M3 receptors are widely distributed in both central and peripheral tissues [7]. The structural diversity between the five different mAChR subtypes is attributed to the presence of the residues in the third intracellular loop of the protein [8]. Experiments like Northern blot and in situ hybridization have revealed that there is some tissue specificity in the distribution of receptor subtype mRNAs. Muscarinic subtypes have also been distinguished based on tissue-specific antagonists and have been developed for therapeutic purposes [5].
The M1 mAChR subtype is abundant in the brain and enteric nervous system while the M2 mAChR subtype is mainly expressed in the heart. Peripheral M3 mAChRs are found extensively in smooth muscles of the gastrointestinal and urinary tracts, exocrine glands, and the eye [9]. In the periphery, M4 mAChRs have been found in relatively higher concentrations in the lungs and in lower concentrations in the salivary glands and ileum. Various peripheral and cerebral blood vessels have been used for the study and identification of mRNA for M5 mAChRs [7]. The M1, M3, and M5 subtypes are tightly coupled to the phosphoinositide system, whereas the M2 and M4 subtypes are closely linked to the mechanism of adenylate cyclase inhibition [10].
Many biochemical and histochemical studies have illustrated evolutionary changes in terms of the concentration of acetylcholine in different parts of the brains of the lower vertebrates [11]. Another study [12] has proposed an increasing functional role for acetylcholine in some telencephalic structures, particularly in the basal ganglia and the tuberculum olfactorium in lower vertebrates. The basal ganglia in non-mammalian brains are extremely enriched in AChE (acetylcholine esterase) activity like that in mammals, while differences in the concentration and distribution of this enzyme occur in the cerebellum of the vertebrate brain [13]. Some studies report chicken may have a cholinergic habenulointerpeduncular pathway system identical to that reported in the rat [14] which suggests the existence of cholinergic cell bodies and fibers in the avian brain. The study has confirmed the above results using immunohistochemical localization of choline acetyltransferase in the chicken mesencephalon, which is part of the avian midbrain.
However, despite the characterization and cloning of all muscarinic receptor subtypes in different species, to date, there are no reports of a functional M1 muscarinic receptor in chicken. This article focuses on the avian muscarinic receptors, their subtypes, distribution, expression as well as characterization and reviews the available information about the various research held in this field so far.
2. Structure of avian muscarinic receptors using homology modeling
So far, there are no reported structures for avian muscarinic receptors in protein data bank or any other public domain sites. We used homology modeling to build the receptor structure using protein-BLAST search (Sequence ID for this search are provided with the individual structures - see Figure 1). Homology modeling is used to determine three-dimensional structure of proteins using its amino acid sequence. It is a model used for computational structure prediction of proteins. Afterwards the SWISS-MODEL service (https://swissmodel.expasy.org/) was used to model the tertiary structure using suggested template protein structure. Discovery Studio Client was used to visualize the final model (Figure 1). In the picture the visual similarities and differences between M2, M3, M4, and M5 are visible. By doing nucleotide sequence alignment, it has been shown that there are not many similarities between each of the muscarinic receptors, though acetylcholine can bind with all the receptors. This may be due to the similar sequences in the ligand binding domains of all the four receptors.
Figure 1.
Images of muscarinic acetylcholine receptor subtypes reported in chicken (Gallus gallus domesticus) homology modeled using Swiss model (https://swissmodel.expasy.org/).
3. Comparison of sequences and construction of phylogenic tree of avian muscarinic subsets
Multiple sequence alignment was done with NCBI tool (https://www.ncbi.nlm.nih.gov/blast/) and individual phylogenic tree for each receptor among avian were created using MEGA 11. Respective human receptors were used for comparative purpose (Figures 2–4) similarity between the reported avian sequences as shown in the tables (Tables 1–3). By analyzing Table 1 the percentage identity of mAChR 2 of Columba livia (rock pigeon) with that of Aquila chrysaetos (golden eagle) is 95.5% with maximum percentage similarity and minimum similarity with cholinergic muscarinic receptor 2 of Homo sapiens (human beings). Similarly, Table 3 details gives percentage identity of muscarinic receptor 3 with other species and its respective human receptors. The same applies to Table 4 and Figure 4.
Figure 2.
Phylogeny tree prepared based on sequence similarity of mAChR 2 of C. livia with different species prepared using MEGA11.
Figure 3.
Phylogeny tree prepared based on sequence similarity of mAChR 3 of C. livia with different species prepared using MEGA.
Figure 4.
Phylogeny tree prepared based on sequence similarity of mAChR 4 of C.livia with different species prepared using MEGA11.
Sl No
Description
Scientific Name and Common Name
Percent identity
Accession
1
C. livia cholinergic receptor muscarinic 2 (CHRM2), mRNA
In birds, fundamental pharmacological studies indicate that mAChRs located in the CNS are associated with vision, navigation, metabolism, and central thermoregulation [35]. However, the role of each of the mAChRs subtypes has not been established in either the CNS or peripheral nervous system [36]. Muscarinic receptor subtypes are expressed in cochlear neurons, supporting cells, central auditory neurons [37], avian vestibular hair cells, nerve terminals, ganglion cells, [38] and also in the avian retina [39]. Table 4 narrates the important locations of muscarinic receptors in birds.
4.1 Avian muscarinic receptors in the central nervous system
Even though the information on muscarinic receptor subtype M1 present in avians is few, some studies have given proof for the presence of central muscarinic M1 receptor subtype. A study [20] has reported the role of muscarinic receptor subtypes M1 and M3 involved in carbachol-induced hypophagia in neonatal broiler chicken. Moreover, the study provided first evidence for muscarinic receptor mediated hypophagic effect in domestic fowl and that the hypophagic effect of muscarinergic system is mediated via M1 and M3 receptors, which were similar to previous reports in mammals [40, 41]. In this study, M2 and M4 receptors had no role in feeding behavior in neonatal broiler chicken, but both M2 and M4 receptors had a prominent role in feeding behavior in rat [42]. It is a well-known fact that there is a significant difference on the role of neurotransmitters in the feeding behavior between avian and mammals [20].
Another study [16] was conducted to assess the functional role of muscarinic acetylcholine receptors in chick brain slices using whole-cell patch-clamp recordings of neurons in the lateral spiriform nucleus. The lateral spiriform nucleus (SpL) forms part of the avian basal ganglia system. It receives cholinergic innervation from the nucleus semilunaris, as well as glutamatergic input from the ansa lenticularis subthalamus, GABAergic input from the paleostriatum primitivum and both GABAergic and possibly dopaminergic inputs from the substantia nigra [43]. But their functional roles in influencing motor behavior remain largely unknown, even after depicting the anatomical pathways. Possibly, the ACh released from cholinergic nerve terminals in or close to the SpL enhances the release of GABA by means of nicotinic AChR activation, which is located on GABAergic axon terminals [44]. Similarly, ACh might act simultaneously on muscarinic AChRs also.
Results of their study revealed that bath application of carbachol, a muscarinic agonist, enhanced the frequency of spontaneous postsynaptic currents and produced a pronounced postsynaptic inward current in normal ACSF (Artificial Cerebrospinal Fluid) with a slower onset but more prolonged action. These effects may be due to the possible muscarinic AChRs belonging to the M3 subtype category and are located some distance from release sites, requiring activation of voltage-dependent sodium channels and N-type voltage-dependent calcium channels (VDCCs) to trigger enhanced GABA release. To determine the muscarinic receptor subtype that mediated enhancement of spontaneous GABAergic IPSCs (Inhibitory Postsynaptic Currents), several muscarinic antagonists were used for testing, of which 4- DAMP mustard alone completely blocked muscarine’s effect. As per existing data on 4-DAMP mustard, it exhibits a high affinity for the M3 receptor, whereas its affinity for other subtypes is significantly lower [45]. Moreover, the pharmacological profile suggested that M3 receptors predominantly contributed to the muscarinic enhancement of GABA release, thus giving evidence for the same.
Another study reported a cDNA that encodes a chicken protein that is homologous to mammalian prion protein (PrPc). PrPc in mammals is an altered isoform of the infectious particle prion (PrPsc) thought to be responsible for spongiform encephalopathies in humans and animals. It is a cellular protein of unknown function in mammals. Chicken prion-like protein (ch-PrLP) is expressed in embryos as early as day 6 in the central nervous system, mostly in the motor neurons. It was found that this protein is abundant in preparations of an acetylcholine receptor-inducing activity based on its ability to synthesize nicotinic receptors in cultured myotubes. Hence, according to the study, it is likely that they serve normally in the neuromuscular junction and central nervous system to regulate chemoreceptor numbers [46].
4.1.1 Muscarinic receptors in pigeon brain
The avian nidopallium caudolaterale (NCL), situated in the caudal telencephalon, serves comparable functions to the mammalian prefrontal cortex, although both are not homologous structures. In the last decades, assumed homologies between avian and mammalian brain components has been studied [47]. It assumes that mammalian and avian pallia share a homologous pallial identity that may be derived from a common ancestry [48]. However, this does not imply that cortical or subcortical pallial areas must be exactly homologous to pallial components in birds.
Various researchers have proved that the mammalian prefrontal cortex (PFC) and the avian NCL share several anatomical neurochemicals [49], electrophysiological and functional [50] characteristics. Hence, the similarities between NCL and PFC may likely do not result from common ancestry, but may be due to an evolutionary convergence. In a quantitative analysis of different receptor binding sites, using autoradiography, by labelling the muscarinic cholinergic M1 receptor with pirenzepine and the muscarinic cholinergic M2 receptor with oxotremorine, the study compared the receptor fingerprints of NCL with those of frontal areas in mammals.
ACh is an essential regulator of cortical excitability and plays important roles for arousal, attention, and cognitive processes [51, 52]. These functions are mediated by muscarinic and nicotinic ACh receptors. Cholinergic M1 receptors were highest in humans if compared to macaque monkey, rhesus monkey, rat and pigeon, while M2 and nicotinic receptors showed equal densities [53]. However, pigeons showed an inverted pattern of M1/M2 binding in the NCL compared to other species which suggests an increased inhibitory control on local circuits, this may be a compensating mechanism for the shift to glutamatergic processing which was at highest concentration in the avian nidopallium [54].
4.1.2 Muscarinic receptors in avian nerve fibers
DRG (dorsal root ganglia) is a collection of bipolar cell bodies of neurons, formed when the dorsal sensory root of spinal nerves exits the neural foramina, surrounded by layers of satellite glial cells (SGCs) [55]. DRG neurons are pseudo-unipolar cells. They give rise to one fiber from which both central and peripheral projections derive, forming peripheral and central sensory branches. These branches contain both myelinated and unmyelinated fibers differing in size, conduction velocity, and perception specification, e. g. nociceptive and thermal sensory neurons [56].
Immunocytochemical studies conducted in the chick DRGs has shown that muscarinic receptors are present in almost all neurons of DRG with a Kd value for [3H]QNB (H-3-quinuclidinyl benzilate) comparable to that reported for mAChRs in other tissue with cholinergic innervation. Hence, DRG neurons not only express cholinergic neurotransmission markers, a high-affinity choline uptake system (HACU) [57], but are also muscarinic cholinoceptive [58]. Functional studies using d-tubocurarine in chick dorsal root ganglia have shown that only about 50% of DRG neurons are responsive to acetylcholine and are sensitive to dtubocurarine suggesting their nicotinic nature [59]. Thus, the divergent distribution of both muscarinic and nicotinic acetylcholine receptor types may indicate their different role in DRG neurons.
A similar study has also identified the presence of muscarinic cholinergic receptors and their microanatomical localization in chicken dorsal root ganglia. They used pirenzepine in competition binding experiments, which showed high affinity for the cloned M1 receptor and labels the M1 receptor of the pharmacological classification [3]. Though the absolute specificity of pirenzepine was questioned by many studies for M1 muscarinic cholinergic receptors [60], the sensitivity of [3H]QNB binding to the compound suggests the expression of the M1 receptor subtype in chick DRG.
In another study to establish muscarinic receptors modulate intracellular calcium levels in sensory neurons of chicks, E18 embryonic chicks were treated with muscarinic agonists such as muscarine and oxotremorine which resulted in an increase of intracellular calcium levels in fura-2 AM (fluorescent calcium indicator) loaded DRG neurons. This effect was antagonized by treatment with atropine and not with the same concentration of mecamylamine indicating that the increase in calcium concentration was due to muscarinic receptor activation. To substantiate the above findings, selective antagonists of muscarinic receptor subtypes were tested, and it also indicated that M1 to a greater extent and to a lesser extent M3 receptor subtypes were responsible for the observed intracellular calcium mobilization. These findings suggest a functional role for acetylcholine and muscarinic receptors in sensory transduction [17]. Moreover, second messengers such as cGMP and cAMPs muscarinic modulation have already been reported in DRG neurons by demonstrating the presence of M1 and possibly M3 subtype in the chick dorsal root ganglia [58].
Another study conducted to investigate the presence of mAChRs by immunolabeling neurons, nerve fibers, Schwann cells, and satellite cells in chicken also suggests the presence of mAChR subtypes. It showed a consistent presence of mAChRs in the neuronal plasma membrane, which suggests a probable role for mAChRs during neuronal differentiation ad exchange of information between neurons [61]. In the nerve fibers, mAChR was detected in the initial segment of emerging neuronal fibers at E12, but the unmyelinated axons of both peripheral and central branches were devoid of an immunoreaction product. This indicates mAChRs may not be involved in the transduction of sensory stimuli [62] in early life. Later, in young chicks several unmyelinated fibers, both central and peripheral, become immunopositive. In young chicks, the immunoreaction product was detected in the axoplasm of numerous unmyelinated central axons, suggesting transport of mAChRs towards the nerve endings in the spinal cord.
In the satellite and Schwann cells, at E12 numerous perineuronal satellite cells surrounding the soma of immunopositive and immunonegative neurons were strongly labeled for mAChRs. Reciprocal communication between neurons and glial cells is well established [63]. Various neuroactive substances synthesized and released by glial cells are involved in neuronal differentiation and growth. Similarly, interaction between Schwann cells and axons are also important for the maintenance of structural integrity and functioning of axons. All these suggest a correlation that at early developmental stages of the avian DRG, the mAChRs expressed by satellite and Schwann cells is important to control the morphogenesis of neurons that take part in sensory functions as well as their axons.
4.1.3 Muscarinic receptors in avian Edinger-Westphal nucleus
Choroid in birds is extensively innervated by ciliary ganglion [64]. Edinger-Westphal (EW) nucleus is the source of the parasympathetic preganglionic input to the ciliary ganglion, upon electrical stimulation, increases the choroidal blood flow in pigeons [65]. Various pharmacological investigations suggest that NO (Nitric Oxide) mediates the EW-evoked vasodilatory response [66]. Earlier studies have identified M3 receptors in avian choroid [29], which mediates the tone of vascular beds in the avian choroid probably by the cholinergic-dependent release of endothelium-derived relaxing factor (presumably NO) [67, 68].
The study examined the role and the type of muscarinic receptors within the choroid that is involved in the increases in choroidal blood flow, using electrical stimulation of the nucleus of Edinger-Westphal (EW) nucleus to activate the ciliary ganglion input to choroid in pigeons. M3 receptors were blocked using a selective antagonist, 4-diphenyl-acetoxy-N-methylpiperedine (4-DAMP), it reduced the baseline choroidal blood flow. Simultaneously, atropine, a non-selective antagonist of muscarinic receptors, decreased the EW-evoked responses to a lesser extent than 4-DAMP.
The results of the study suggested a major role of M3 type muscarinic receptors in the EW evoked increases in choroidal blood flow in pigeons [30]. Based on another finding that the input of ciliary ganglion to choroid does not synthesize NO, but inhibitors of NO production do block EW-evoked choroidal vasodilation [66], it seems likely that the M3 receptors acted on by 4-DAMP are present on choroidal endothelial cells and mediate choroidal vasodilation via stimulation of endothelial release of nitric oxide.
5. Avian muscarinic receptors in sensory structures
5.1 Muscarinic receptors in avian vestibular end organs
Muscarinic acetylcholine receptor subtype expression in avian vestibular hair cells, nerve terminals and ganglion cells has been conducted based on the patch clamp recordings from pigeon native hair cells with carbachol, a cholinergic agonist, resulted in reduction of the current through the inward rectifier pKir2.1 channel [32]. The cilia on the hair cells and the associated structures are important during sensory transduction.
They cloned and sequenced pigeon mAChR subtypes M2–M5 in the pigeon vestibular end organs (semicircular canal ampullary cristae and utricular maculae), vestibular nerve fibers and the vestibular (Scarpa’s) ganglion and studied the expression of all five mAChR subtypes (M1–M5) in the pigeon vestibular end organs (semicircular canal ampullary cristae and utricular maculae), vestibular using tissue immunohistochemistry (IH), dissociated single cell immunocytochemistry (IC) and Western blotting (WB). In the study, vestibular hair cells, nerve fibers and ganglion cells expressed all five (M1–M5) mAChR subtypes. mAChRs M1 and M5 were found on the nerve terminals, supporting cells, and cilia of hair cells. And mAChRs M1, M3 and M5 were expressed on cuticular plates, myelin sheaths and Schwann cells. M2 and M4 mAChRs were seen on the nerve terminals. M2 was also present on the cuticular plates and supporting cells [38].
Immunohistochemistry and Immunocytochemistry results were consistent with results from WB of the dissociated vestibular epithelia, nerve fibers and vestibular ganglia. It is clear from the study that the neuronal components of the labyrinth exhibit significant co-expression of the subtypes. Even though the study does not give data on quantitative expression of M1–M5 but do indicate that the mAChRs are widely present and co-expressed on elements in the vestibular peripheral system. The additional possibility of mAChR expression on efferent fibers and terminals forming autoreceptors should be analyzed using further research in this area.
Acetylcholine receptors often perform autocrine and neuronal activities [69]. Control of cell growth and proliferation and release of chemical mediators [70, 71] are the major autocrine functions. These functions are important in vestibular hair cell regeneration or maintenance and replenishment of endolymph and perilymph. Non-neuronal cholinergic function is attributed by the expression of mAChR subtypes on the supporting cells and Schwann cells [72].
5.2 Muscarinic receptors involved in chick myopia
Various studies conducted in the chick model of myopia has proved that the most effective anti-muscarinic agents for myopia includes the non-selective agents like atropine [73] and oxyphenonium [74], followed by the partially selective muscarinic antagonists M1 and M4 selective pirenzepine [75] and the M2 and M4 selective himbacine [76]. In a study using the selective M4 muscarinic receptor antagonist MT-3, it was effective in inhibiting form-deprivation myopia in the chick by means of inhibition of vitreous chamber elongation, the major structural cause of myopia, associated with inhibition of choroidal thinning in myopic chicks. While in certain studies using muscarinic antagonists such as atropine and pirenzepine, they also produced similar efficacy in reducing myopia, at doses substantially higher than that would be considered necessary for a muscarinic receptor-based mechanism, namely at micromolar concentrations.
But in this particular study, since the muscarinic antagonists applied were highly selective for the M4 and M1 receptors, the doses were calculated to be at nanomolar concentrations at the receptor level. Similarly, upon applying the highly selective M1 muscarinic antagonist MT-7, it had no inhibitory effect on form-deprivation myopia in chick, deriving a conclusion that the chick lacks an M1 receptor, as supported by their findings [26].
In a similar experiment involving the chick myopia model, attempts were made to isolate and process RNA and genomic DNA for the evidence of a functional M1 muscarinic receptor in chicken. However, the results produced no evidence for the same, which itself indicates that the mRNA template necessary for the production of the M1 receptor protein is unlikely to be present in chick. Furthermore, it could be concluded that the chick lacks a gene or promoter sequence for the M1 receptor. Moreover, the study was consistent with previous report, which demonstrates a tenfold affinity of pirenzepine for the chick M2 receptor subtype than its mammalian counterpart [77]. Hence, the study suggests the possibility that pirenzepine inhibits myopia progression via the M2 receptor in birds and via the M1 receptor in mammals. Furthermore, it also suggests the possibility that muscarinic antagonists which prevents myopia in chicks mediates its action through another muscarinic subtype, probably the M4 subtype or through non-specific or non-receptor mediated mechanisms [25].
Moreover, this can be consistent with another finding which localized the presence of G protein-coupled receptor kinases (GRKs) in the avian retina [39]. GRKs are enzymes that are involved in the phosphorylation of serine/threonine residues in the carboxy-terminal of various of agonist-occupied G protein-coupled receptors [78, 79]. Retinal morphology and electrophysiology are relatively well characterized, since it is an excellent model for neurochemical studies of the nervous system since its development. At least six enzymes have been cloned and were extensively characterized from mammals [80]. Of these, mammalian retinal rods and cones expressed GRK1 [81]. In the chicken retina, two different types of photoreceptors expressed a novel GRK1 [82]. However, not only muscarinic receptors act via GPCR mediated mechanism but also dopaminergic D1, D2, D4 and D5 receptors [83], adenosine A1 and A2 receptors [84] and metabotropic glutamate receptors [85], among others, were characterized in this tissue.
In the study, G protein-coupled receptor kinases 2, 3 and 5 were expressed in different regions and cell populations of the chick retina. While immunoreactivity of GRK2 was found over all types of neurons of the retina and over both plexiform layers, immunolabeling for GRK3 was restricted to the inner portion of the retina, over the inner plexiform layer and amacrine and ganglion cell bodies. However, immunoreactivity for GRK5 was only found in amacrine and Muller glial cells bodies and processes [39].
Another study characterized a muscarinic receptor in chicken trachea controlling secretion of chlorides. In the study the chicken trachea was stimulated to secrete chloride ions by the application of acetyl choline and this was completely inhibited by bumetanide suggesting the presence of a functional muscarinic receptor in the avian trachea. In the study they classified the receptor subtype as M4, which probably is involved in ion transport on exocrine glands and mucosal cells [31].
7. Muscarinic receptors in avian gastrointestinal system
Characterization of muscarinic receptors in avian smooth muscles has been done by many researchers, especially in the ileum of chicken using functional and binding studies. Decades back, a contractile response to carbachol antagonized by atropine had been studied in the chick ileum [86]. In the functional studies, the affinities obtained exhibited good agreement with the existence of a functional M3 muscarinic receptor subtype in the ileum of chicken, however the findings were in direct contrast to the binding experiments, in which the single binding site appeared to be the muscarinic M2 receptor subtype. Hence, even though the contractile response was mostly due to a functional M3 receptor subtype, analysis of the competition binding curves suggested the presence of a uniform population of the muscarinic M2 receptor subtype also even though it did not contribute to the contractile response [28].
8. Muscarinic receptors in avian cardiovascular system
As mentioned above, initially the only available data on chicken muscarinic receptors was that of the M2 muscarinic receptor subtype. But many ex-vivo experiments have given proof for the existence of avian correlates in atria of chick for muscarinic M2 receptor [77], M3 receptors in atrium and ventricles [23] and M5 receptor subtype in embryonic chick heart and brain [24]. The potent muscarinic cholinergic antagonist 3 -quinuclidinyl benzylate (QNB) has been used to detect and quantify muscarinic receptors as early as day 3 in ovo in the developing chick heart [87]. The study found an exponential increase in 3 -quinuclidinyl benzylate (QNB) binding sites, which reduced at day 18 in ovo. However, the receptor density and subtype were not investigated in the above study.
Another study determined the effect of exposure of cardiomyocytes from chicken embryos for 3 days to the beta adrenoceptor agonist, isoproterenol. In the study, the 3 days exposure induced an increase in the level of muscarinic acetylcholine receptors by about 30% in chicken cardiomyocytes [88].
Another study found out the inotropic response of muscarinic acetyl choline receptors to the stimulation of isolated chick ventricular myocardium at various developmental stages. The study also pharmacologically characterized the receptor subtype involved in embryonic chick ventricles. Carbachol produced positive inotropy in embryonic chick ventricles at micromolar concentrations, whereas in hatched 1–3-day old chick ventricles it produced negative inotropy at nanomolar concentrations. However, in the 19–21-day-old embryos, neither positive nor negative inotropy was observed. Conclusions were made by comparing the pA2 values that positive inotropy is most likely due to muscarinic M1 receptors and the negative inotropy is most likely mediated by muscarinic M4 receptors [22].
9. Muscarinic acetylcholine receptors in the avian salt gland
Unlike other vertebrate exocrine glands, the avian salt gland secretes an effluent that contains only trace amounts of protein or other macromolecular species, which makes it a unique model for the study of exocrine secretion of electrolytes [89]. This hypertonic secretion principally contains sodium and chloride ions in the rage of 500 to 900 mEq/l concentrations [15]. Administration of acetylcholine or methacholine in herring gulls stimulated salt gland secretion, while secretion in response to either a parenteral salt load or to a direct stimulation of the secretory nerve is blocked by injection of atropine, which suggests the role of muscarinic receptors responsible for its secretory function. In order to demonstrate and characterize these receptors in avian salt gland, radiolabeled muscarinic antagonist [H]quinuclidinyl benzilate ([3H]QNB) was used in ducklings under fresh water and salt water conditions.
Characterization of these receptors using the radiolabeled antagonist, [3H]QNB, showed them to be similar to muscarinic receptors from various mammalian sources, including rabbit iris, rabbit heart, rat parotid gland, and rat brain [90]. Regardless of conditions, since the DNA content of individual cells in the salt gland remains the same in case of salt stress, relating [3H]QNB binding to DNA allows calculation of average number of receptors per cell. Upon conducting this calculation, it became evident that individual salt gland cells in salt water contains approximately three times as many muscarinic receptors as that of fresh water glands [15]. These results thus provide direct evidence for de novo synthesis of muscarinic cholinergic receptors during the plasma membrane hypertrophy that typifies the response of salt gland epithelial cells to chronic salt stress.
The first report of muscarinic acetylcholine receptors in Japanese quail intestine was evaluated by recording the contractile responses of quail ileum to the agonist and agonist in presence of antagonists, also relaxant effect of muscarinic receptor antagonists with submaximal contraction of Ach using an isometric transducer. In the study, EC50 values of ACh increased in the presence of atropine (nonselective muscarinic antagonist) and pirenzepine (M1/M2 muscarinic antagonist) compared to EC50 value of ACh alone. Also, the EC50 value of Ach was higher in the presence of atropine when compared to EC50 of ACh in presence of solifenacin (M3 muscarinic antagonist). It was also found that EC50 of ACh was increased 3.48 times in presence of atropine, 2.65 times in presence of pirenzepine and 1.56 times in presence of solifenacin. These findings indicate that the muscarinic receptor subtypes responsible for contraction of small intestine in Japanese quail is contributed by both M2 and M3 muscarinic receptor subtypes, and it was substantiated using molecular studies which revealed the absence of M1 receptor gene in Japanese quail and this finding is in accordance with the reports in chicken. The results of the study indicated that muscarinic receptors are distributed with the same propensity in quails like that of other avian and other mammalian species [34].
11. Conclusions
Several research have revealed that different bird species like chicken, pigeon and herring gulls have numerous functioning muscarinic receptors. The receptors in these species are mostly found in the central nervous system (dorsal root ganglia, basilar artery) and heart, as well as in sensory structures like the vestibular periphery and in avian salt glands respectively. Several studies have found them in the trachea, proventriculus and in smooth muscles of the intestinal tissue (ileum, rectum). The paper also reviews the existence of muscarinic receptors in quail ileum, a first report of its own in quail. Major receptor subtypes identified in avians are M2, M3, M4 and M5 except for M1 receptors present in dorsal root ganglion, atria and ventricles of heart and vestibular periphery. Even though, the muscarinic receptor subtypes in avians have been identified and characterized, the transduction mechanisms and functional contribution of each receptor subtypes has not been studied properly, which is a major shortcoming of researches in avian muscarinic receptors. For the goal of organizing the prospective neurophysiological and pharmacological research of cholinergic transmission in this species, it is crucial to establish the functional role of cholinergic systems in avians. However, in spite of the findings discussed here, rigorous studies are required in this field to further investigate the function and expression of mAChRs in avians.
Conflict of interest
The authors declare no conflict of interest.
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