alexa Molecular Interactions between Ligands and Nicotinic Acetylcholine Receptors Revealed by Studies with Acetylcholine Binding Proteins

ISSN: 2157-7544

Journal of Thermodynamics & Catalysis

  • Review Article   
  • J Thermodynam Cat 2012, Vol 3(4): 116
  • DOI: 10.4172/2157-7544.1000116

Molecular Interactions between Ligands and Nicotinic Acetylcholine Receptors Revealed by Studies with Acetylcholine Binding Proteins

Hugo R. Arias*
Department of Medical Education, College of Medicine, California Northstate University, CA, USA
*Corresponding Author: Hugo R. Arias, Department of Medical Education, College of Medicine, California Northstate University, CA, USA, Tel: 916-686-7300, Fax: 916-686-7310, Email: [email protected]

Received Date: Oct 12, 2012 / Accepted Date: Oct 18, 2012 / Published Date: Oct 22, 2012


Nicotinic acetylcholine receptors (AChRs) are the best characterized ion channels representing the Cys-loop ligand-gated ion channel superfamily. Studies using Torpedo AChRs in the closed and open states andacetylcholine binding proteins (AChBPs) from different origins have elucidated the most important structural and functional features of the agonist/competitive antagonistbinding sites. The first step in recognizing the neurotransmitter ACh and other agonists is fundamental in the process of agonist-induced activation, including the opening of the intrinsic cation channel. The AChBP studies demonstrated that Loop C is an important structural feature that is modified by ligand binding. These studies defined important pharmacologic features of AChR ligands, including the differences between full and partial agonists, agonists and competitive antagonists, peptidic and non-peptidic ligands, and between high affinity and high selectivity. The studies showing the structural mechanisms by which specific ligands can activate, inhibit, and potentiate different AChR subtypes could be of therapeutic importance.

Keywords: Cys-loop ligand-gated ion channels; Nicotinic acetylcholine receptors; Acetylcholine binding proteins; Loop C; Crystallography


AChR: Nicotinic acetylcholine receptor; AChBP: Acetylcholine bound protein; 5-HT: 5-Hydroxytryptamine (serotonin); ACh: Acetylcholine; GABA: γ-aminobutyric acid; DMXBA: 3-(2,4 dimethoxybenzylidene)-anabaseine; a-BT: a-bungarotoxin; κ-BTx: κ-bungarotoxin; a-CbTx: a-cobrotoxin; MLA: Methyllycaconitine; d-TC: d-Tubocurarine; DHßE: Dihydro-ß-erythroidine; SPX: 13-desmethyl spirolide C; GYM: Gymnodimine A; a-CTx: a-conotoxin; MTSET+: 2-(trimethylammonium)ethylmethanethiosulfonate; MMTS: methylmethanethiosulfonate; Ls: Lymnaeastagnalis; Ac: Aplysiacalifornica; Bt: Bulinustruncates; Bg: Biomphalariaglabrata; Ct: Capitellateleta


A vast amount of evidence indicates that nicotinic acetylcholine receptors (AChRs) are important for the homeostasis and function of our body. AChRs are cation channels members of the Cys-loop ligand gated ion channel superfamily, including type 3 serotonin (5-hydroxytryptamine; 5-HT) cation channels as well as anion channels such as type A and C γ-aminobutyric acid (GABA) and glycine receptors [1-3]. A large number of subunits have been cloned for all members of the Cys-loop super family from vertebrates and invertebrates (Ligand-gated ion channel database, [4]. In vertebrates, AChR subunits are classified in two types, a (i.e., a1-a10) and non-a (i.e., ß1- ß4,γ, δ, and e), where a subunits contain a disulphide bridge in the binding site, whereas non-asubunits do not. AChRs can be formed by the same subunit comprising homomeric receptors [e.g., a7, a8 (expressed only in chicks), and a9] or by different subunits comprising heteromeric receptors (e.g., a4ß2, a3ß4) [5,6]. However, not all possible subunit arrangements are functional. For example, the neuronal AChR subunits a2-a4, ß2, and ß4 can co-assemble in pair wise combinations forming functional AChRs (e.g., a4ß2, a3ß4). Although the a9 subunit is actually expressed in the cochlea, the functional receptor in hear cells is the a9a10 AChR subtype. Although the homomerica7 AChR is functional, a7 AChRs containing other subunits (e.g., a7ß2) have been characterized endogenously and probably these are the native AChRs. Each a5, a6, and ß3 subunit does not form functional AChRs by binary combinations with another subunit, instead they prefer ternary combinations [e.g., (a4)2a5(ß2)2]. AChRs can even be formed by assembling four different subunits [e.g., a4a6a5(ß2)2], but there is no evidence of a receptor subtype formed by five different subunits. In addition, two different stoichiometries of the a4ß2 AChR (and probably for the a3ß4 AChR as well), (a4)3(ß2)2 and (a4)2(ß2)3, have been found in heterologous [7-10] and endogenous [11] cells. The (a4)2(ß2)3 stoichiometry is more sensitive to the action of agonists including agonist induced up-regulation, desensitizes less rapidly, and has lower Ca2+ permeability compared to that for the (a4)3(ß2)2 stoichiometry. The use of subunit concatemers might be useful in determining the subunit composition and stoichiometry of native AChRs [5].

Vertebrate AChRs are expressed in neuronal and non-neuronal tissues. In the peripheral and central nervous systems, presynaptic AChRs modulate the release of several neurotransmitters, including ACh, 5-HT, GABA, dopamine, norepinephrine, and glutamate, whereas postsynaptic AChRs mediate rapid transmission by converting a chemical signal into membrane depolarization (i.e., electrical signal), or trigger cytoplasmic cascades. These combined actions modulate several important functions in our body, including cognition, memory, pain perception, auditory response, and muscle contraction. In nonneuronal tissues, AChRs are involved in angiogenesis and immune responses [12,13]. Since AChRs are involved in such important physiological functions, their improper activities (e.g., decreased number, mutations, or hypo/hyperactivity) can produce several diseases, including Alzheimer’s disease, Parkinson’s disease, schizophrenia, nocturnal frontal lobeepilepsy, attention deficit hyperactivity disorder, Tourette’s syndrome, drug and nicotine addictions, depression and anxiety, myasthenia gravis, myasthenic syndromes, tumor growth, and decreased immune response [2,3,12-15].

Several AChR subunits have been also cloned in insects and invertebrates [16]. In invertebrates, AChRs have become key elements for the development of neuroactive pesticides. For example, several neonicotinoids (e.g., imidacloprid, clothianidin, and thiacloprid) have insecticide activities but extremely low mammalian toxicities due to their high affinity and specificity for insect AChRs [16].

Breakthroughs In The Study Of AChRs

Three main breakthroughs in the last 10 years have helped in elucidating the functionally relevant structural features of AChRs and their cousins [1,17,18]: (1) the Torpedo AChR structures in the closed [19] and open [20] states, showing the main features at the extracellular, transmembrane, and intracellular domains (Figure 1 and 2) the crystal structures of several acetylcholine binding proteins (AChBPs) showing details of the binding sites for agonists and competitive antagonists [21], and (2) the recently elucidated prokaryotic cation channels showing subtle differences between the open and closed conformations, as well as between activated (i.e., with several primary amines [22]), blocked (i.e., with several cations and open-channel blockers [23]), and inhibited (i.e., with several allosteric modulators [24]) states. Table 1 summarizes the different three dimensional structures obtained so far for Torpedo AChRs and different AChBPs bound to a variety of ligands.


Figure 1: Torpedo AChR model showing the structural differences between the open (magenta) and closed (blue) states at 6.2 Å resolution (modified from [20] ). Only subtle differences can be seen between both conformational states. AChRs are formed by three main domains: The extracellular domain shows the β-strands forming the β-sandwich structure.The transmembrane domain is formed by 20 α-helices, four α-helices per subunit. The cytoplasmic domain is the smallest domain.


Figure 2: Structure of AChBP from Capitella teleta (Ct-AChBP) complexed with the partial agonists lobeline (A-C) and varenicline (D) respectively (modified from [30]). AChBP-lobeline structures showing the N-terminus pointing away (A) or toward (B) the viewer, and the subunit interface (principal face in yellow and complementary face in blue) towards the viewer (C). Each of the five subunits is displayed in a different color. Oxygen, red; nitrogen, blue; sulfur, green. The glycosyl chain N-linked to N122 is shown in magenta. The paucimannose chain is composed of N-acetylglucosamine (NAG), α-Dmannose (α-MAN), and β-D-mannose (β-MAN) (D) Ct-AChBP-varenicline complex. Lobeline and varenicline complexed with Ct-AChBP are shown as spheres, whereas the insets show the electron density of each molecule.

Structurally, AChRs are pentameric proteins with an extracellular domain that carriesthe binding sites for agonists (e.g., the neurotransmitter ACh and nicotine) and competitive antagonists [e.g., methyllycaconitine (MLA)]. In addition to these orthostericsites, several additional sites have been characterized in this domain for allosteric modulators [25,26]. The transmembrane domain, specifically the M2 transmembrane segments from each subunit, forms the ion channel that is essential for cation flux (i.e., Na+ and Ca2+influx and K+ efflux), finally producing membrane depolarization, and in the case of Ca2+, triggering different intracellular pathways.

The ion channel is the main domain for the interaction with a very broad group of compounds called noncompetitive antagonists [14,15,27]. In addition, several binding sites for negative allosteric modulators have been characterized between the four M1-M4 transmembrane segments [25,26].

Agonist binding at the extracellular domain triggers the opening of the ion channel, an intrinsic process called gating [1]. Determining how the agonist-induced structural changes, that start in the agonist binding pocket, are propagated through a distance of ~50 Å to the gate is central for the understanding of the receptor function. One of the AChR domains that have recently attracted attention among researchers is the extracellular–transmembrane interface. This is a very unique transitional zone where ß-sheets from the extracellular domain merge with a-helices from the transmembrane domain, finally allowing functional communication between both domains [1,25,26].

Overall Structure Of AChRs

AChRs are pentameric proteins where the subunits are arranged around an axis perpendicular to the membrane, and each subunit shares a basic scaffold composed of: (1) a large N-terminal extracellular domain of ~200 amino acids; (2) three transmembrane domains (M1-M3) separated by short loops; (3) a cytoplasmic loop of variable size andamino acid sequence; and (4) a fourth transmembrane domain (M4) with a relatively short and variable extracellular COOH-terminal sequence (Figure 1). AChRs are therefore built on a modular basis, with the extracellular domain containing the agonist binding sites, the transmembrane domain containing the pore, selectivity filter, and channel gate, and the cytoplasmic domain performing additional modulatory activities [19,20].

Recent structural studies have provided details of the three dimensional structure of AChRs and consequently for other members of this receptor superfamily. In particular, the structural model of the Torpedo AChR at 4 Å resolution [19] has revealed important information and has been invaluable in the interpretation of functional and pharmacological data. Although no structural information is available for any Cys-loop receptor at the atomic resolution level, the extracellular domain of the AChRa1 subunit has been resolved at 1.94 Å [28]. Additional high resolution structural information has become available from studies of proteins which show close structural similarity to AChRs, including soluble AChBPs from a variety of animals from the Mollusca [21,29] and Annelida [30] phyla [1,17], as well as prokaryotic proton-gated ion channels from the bacteria Erwiniachrysanthemi (ELIC) and Gloebacterviolaceus (GLIC), respectively [1,18]. The characterization of GLIC showed that it forms a cation-selective channel that is activated by protons, where currents do not decay during activation, suggesting no or very slow desensitization [31]. Recent results using ELIC showed that different primary amines, including GABA, can also activate this channel [22]. The ELIC X-ray structure shows 16% sequence identity to aAChR subunits. In general, the extracellular domain is very similar to its eukaryotic counterpart and to AChBPs, but lacks the N-terminal a-helix. However, the putative binding site andseveral of the aromatic residues found in AChRs are conserved. The central part of the Cys-loop is also conserved but lacks the flanking disulfide-bridge.

The Extracellular Domain

The solution of the high-resolution structure of the AChBP from Lymnaeastagnalis (Ls-AChBP) was agiant step forward for our knowledge of the structure of the extracellular domain of AChRs [1,17,21]. Since then, several other AChBPs from mollusks and annelids have been characterized (Table 1). In general, AChBPs lack the transmembrane region but contain many of the structural features that give AChRs their unique signature and have therefore become functional and structural surrogates of the extracellular domain of the Cys-loop receptor superfamily. The AChR extracellular domain contains 210 amino acids and shares ~15-24% sequence identity to aligned sequences of the amino-terminal, extracellular halves of Cys-loop receptor subunits. Each AChBP monomer consists of an N-terminal a-helix, two short 310 helices, and a core of 10 ß-strands that form a ß-sandwich structure. The inner ß-sheet isformed by the ß1, ß2, ß3, ß5, ß6 and ß8 strands, and the outer ß-sheet by the ß4, ß7, ß9 and ß10 strands. The N- and C- terminals are located at the top and bottom of the pentamer, respectively. In Cys-loop receptors, the end of ß10 connects to the start of M1. Located at the bottom of the subunit; the linker between ß6 and ß7 strands is the signature Cys-loop found in all members of the superfamily, including bacterial ion channels.

Structure Ligand bound Conformational state PDB Resolution (Å) Reference
AChR None Closed (Resting) 2BG9 4.0 [19]
Closed (Desensitized)
α1 α-BTx Open 2QC1 1.94 [28]
α1-13-residue peptide α-BTx - 1HCB 1.8 [52]
Ls-AChBP HEPES Intermediate 1I9B 2.70 [21]
Ls-AChBP α-CbTx Open 1YI5 4.20 [54]
Ls-AChBP DHβE Closed 4ALX 2.51 [42]
hα7/Ls-AChBP chimera n-Acetyl-d-glucosamine
Bt-AChBP CAPS Intermediate 2BJ0 2.0 [55]
Ac-AChBP None
Closed; g-to-t
Ac-AChBP α-CTxImI Open 2C9T 2.2 [57]
Ac-AChBP α-CTxTxIA(A10L) Open 2UZ6 2.4 [50]
Ac-AChBP Cocaine
Ac-AChBP Imidacloprid
Ac-AChBP Clothianidin
Ac-AChBP Sulfate Coordinated with Lys residues 3GUA 3.10 [59]
Ac-AChBP Anabaseine
Ac-AChBP None
Compound 31
Compound 35
Apo; g
Ac-AChBP Metocurine
Ac-AChBP Fragment 1
Compound 3
Compound 4
Compound 6
Open; g
(Y53C mutant)
MMTS and ACh
  Ac-AChBP   d-TC
hα7/Ac-AChBP chimera Mutant I
Mutant II + MLA
Mutant III + MLA
Ac-AChBP Compound 18 (complex I)
Compound 6 (complex II)
Compound 6(complex III)
Ac-AChBP Varenicline
Ac-AChBP Triazole 18 - 4DBM 2.30 [64]
Pentagonal dodecahedron 4AOD
Ct-AChBP None Apo - Low resolution [65]
Ct-AChBP Varenicline
Intermediate; g-to-t
Closed; g-to-t
Ct-AChBP Compound 5 Intermediate 4B5D 2.3 [66]

AChRs are obtained from Torpedo marmorata electric fish.
AChBPs are obtained from Lymnaeastagnalis(Ls), Aplysiacalifornica(Ac), Bulinustruncatus(Bt), Biomphalariaglabrata (Bg), and Capitellateleta(Ct), respectively.
The close (i.e., contracted) and opened (i.e., extended) states of Loop C in the AChBP-ligand complexes indicate the active/desensitized (i.e., agonists) and resting (i.e., antagonists) states, respectively. Several ligands, including partial agonists, adoptan intermediate configuration between that for full agonists and competitive antagonists, where as allosteric modulators (e.g., cocaine and galantamine) do not produce any apparent change on Loop C. The g-to-t (also called Tyr-flip) conformational state corresponds to the opening of the lobe line pocket. The g state is the closed lobeline pocket, whereas in the endoconfiguration the ligand is unable to induce the opening of the lobe line pocket.

Table 1: Conformation states of AChRs and AChBPsin unbound and bound conditions.

Agonist binding sites are located at the subunit interfaces [1-3,17,18]. Each binding site isformed by two faces. One face, called the principal or “positive” face at the a-subunit, is formed by ß-strands connected by three loops harboring key aromatic residues [i.e., LoopA (ß4ß5 loop), Loop B (ß7ß8 loop), and Loop C (ß9ß10 loop)]. The complementary or “negative” face at the non-a-subunit contributes with three ß-strands clustered in segments by Loops D-F. Thus, key residues (corresponding to Torpedo a1-subunit) from the principal face come from Loop A (Trp86 and Tyr93), Loop B (Trp149 and Gly153) and Loop C (Tyr190, Cys192, Cys193 and Tyr198). The complementary face is formed by residues from Loop D (Trp55 and Asp57), Loop E (Leu109, Arg111, Thr117 and Leu119), and Loop F (Asp174 and Glu176) (residues from the Torpedo δ- or γ-subunit) [1,21,32].

The ancestral Cys-loop receptor was likely homomeric and contained five identical binding sites, similarly to present day homomeric receptors, such as a7 and 5-HT3A receptors [32,33]. Evolution led to the appearance of new subunits which lost the ability to form agonist binding sites, giving rise to heteromeric receptors with fewer than five binding sites. The prototypic heteromeric receptors, muscle AChR and GABAARs, contain only two agonist binding sites, which have to be both occupied to allow appropriate gating. Although homomeric receptors contain five identical binding sites, it was shown that occupancy of only three of the five sites is required for optimal activation [34].

Structural Changes Of Loop C When Interacting With Agonists And Small Competitive Antagonists

Several lines of evidence indicate that ligands at the agonist binding site are stabilized by p-cation, dipole-cation, hydrogen bonding, and van der Waals interactions [35,36]. Agonist interaction produces activation (opening) of the AChR ion channel. The transition from the resting to the activated state is relatively fast, although the time regime is different among receptor subtypes. Molecular details about the activation process were determined by studies onAChBP- and AChR-bound ligand structures. For example, structural differences between the closed and open states permitted to determine that ACh elicits clockwise rotation of the inner ß-sheet with respect to the outer ß-sheet, causing tilting of the Cys-loop (Loop C) away from the fivefold axis [20].

The results using AChBPs with different ligands indicate that Loop C from the principal face is in an extended (“open”) conformation in the resting AChR (no agonist), whereas in the presence of full agonists, Loop C is contracted (“closed”) and caps the entrance to the binding cavity, trapping the agonist [36,37]. Cysteine substitution and subsequent oxidation studies on Loop C of muscle AChRs indicate that Loop C capping is involved in the transition of the closed receptor to an activated pre-open intermediate state [38].

The interaction of several agonists (full and partial), competitive antagonists, and allosteric modulators with their binding sites was studied in minute detail by co-crystallization of various ligands with AChBPs from different species (Table 1). In addition to structural differences between ligands, diverse AChBP selectivity for several ligands was observed [17,39]. The structural basis to distinguish high affinity vs high selectivity for different ligands [e.g., d-tubocurarine (d-TC) and strychnine] was also described [40]. Another important structural difference is the interaction between full and partial agonists. In general, AChBP-agonist complexes show a fully contracted (closed) state, whereas AChBP-antagonist complexes show a more extended (open) state. However, additional experiments comparing the full agonist nicotine and the partial agonists cytisine and varenicline could not discriminate any variation in the Loop C closure [41]. In particular, varenicline interacts with highly conserved aromatic amino acids at the principal face of the binding site, and with less conserved hydrophobic residues at the complementary face (e.g., at Loop E) [30]. Interestingly, dihydro-ß-erythroidine (DHßE), a potent competitive antagonist of ß2- containing AChRs, imposes closure of the Loop C as agonists do, but also induces a structural change perpendicular to the observed Loop C movements [42]. To illustrate some important differences between agonists and competitive antagonists, AChBP structures complexed with the partial agonists varenicline and lobeline (Figure 2) and the competitive antagonists DHßE (Figure 3).


Figure 3: Structure of AChBP from Lymnaea stagnalis (Ls-AChBP) complexed with the competitive antagonist dihydro-β-erythroidine (DHβE) (modified from [42] ). (a) Structure of DHβE. (b) Complex viewed along the five-fold symmetry axis. The five subunits are shown in different colors and DHβE in red spheres. (c) Interfacial binding pocket formed by the highly conserved aromatic residues Tyr89, Trp143, Tyr185, and Tyr192 from the principal side of the interface (yellow) and Trp53 from the complementary side (limon). DHβE is shown in red, and hydrogen bonds between DHβE and its surroundings are shown as stippled lines.

Some other ligands produce an intermediate state, whereas the allosteric modulators cocaine and galantamine do not produce any apparent conformational change [43]. For example, the dibenzosuberylatropine analogs, compounds 31 and 35, which pharmacologically act as mixed competitive/noncompetitive antagonists on AChRs [44], induce an intermediate open configuration of Loop C, suggesting an intermediate resting/activated state. Interestingly, partial agonists of the a7 AChR such as DMXBA [3-(2,4-dimethoxybenzylidene)- anabaseine], its hydroxyl metabolite 4OH-DMXBA, and tropisetron, display multiple orientations within the five binding sites and adopt an intermediate configuration between that for full agonists and competitive antagonists [45]. Nevertheless, the partial agonist a-lobeline induces a strong Loop C closure [30,46]. More specifically, the interaction of a-lobeline with the AChBP site opens a sub pocket to accommodate the a-hydroxyphenetyl moiety, inducing the g-to-t (also called Tyr-flip) conformational state [39], where the g state is the closed lobeline pocket, whereas in the endo configuration the ligand is unable to induce the opening of the lobeline pocket. These results suggest that the different occupation and orientation between full and partial agonists may produce distinct conformations of Loop C. Interestingly, a-lobeline binds to Ct- and Ac-AChBPs at different configurations [30,46]. In Ct-AChBP, the a-lobelinepiperidine ring adopts a chair conformation and its hydroxyl group is in the S-configuration, whereas in the Ac-AChBP the ring adopts a half-chair conformation and its hydroxyl group is in the R-configuration.

The AChBP structures in the absence of ligands or buffer molecules (i.e., Apo) show that the Loop C is more flexible than that in the presence of ligands, and that there are ordered water molecules filling the pocket. This structure is reminiscent to the Torpedo AChR model in the resting state [19]. Instead, buffer molecules (e.g., HEPES, CAPS) in the binding pocket move Loop C in a more open configuration, suggesting an intermediate state [46].

Structural Changes Of Different Loops When Interacting With Large Competitive Antagonists

Competitive antagonists overlap the agonist sites and inhibit their pharmacological action. In addition to this competitive (steric) mechanism, there is information that some antagonists [e.g., a- and κ-bungarotoxin (a- and κ-BTx), a-cobrotoxin (a-CbTx), and methyllycaconitine (MLA)] maintain the AChR in the resting state [36,47,48], probably inhibiting the gating process. At the molecular level, MLA, the potent competitive antagonist of the a7 AChR, induces an intermediate open configuration of Loop C [46]. Although the Loop C conformation distinguishes agonists from competitive antagonists, additional results indicate thatLoop F is another structural component responsible for ligand selectivity; especially for antagonists [45]. Although the toxins 13-desmethyl spirolide C (SPX) obtained from Alexandriumostenfeldii and gymnodimine A (GYM) obtained from Kareniaselliformis are among the most potent non-peptidic antagonists (i.e., binding affinities in the subnanomolar concentration range), they are nonselective antagonists, probably because they interact in less proportion with Loop F in the complementary face [49]. Crystallographic information supports the view that in general peptidic antagonists (i.e., snail and snake neurotoxins) maintain the AChBP in the resting state, whereas other nonpeptidic antagonists induce an intermediate state (Table 1). Different snail a-conotoxins (a-CTxs) also differ in their intrinsic orientations [50], probably resembling their receptors electivities.

The Ac-AChBP-Y53C mutant binds to Cys-modifying agents by different manners [51]. In this regard, MTSET+ [2-(trimethylammonium)ethylmethanethiosulfonate] produces a less constricted Loop C, similar to peptidic antagonists, whereas the conformation of Loop C in the presence of MMTS (methylmethanethiosulfonate) and ACh resembles that for agonists (Table 1). Since the location of the conserved amino acid Y53 is at Loop D, these results also emphasize the concept of concerted interactions between Loops D and C. Another important difference between agonists and antagonists is that cation–p interactions are formed between the conserved Trp residue in Loop B (i.e., W143 in Ls-AChBP) and agonists such as (-)-nicotine [53], whereas no cation–p interactions are formed with antagonists such as a-CTxs [46,50,56,57] and neonicotinoids [16,58]. Taking into account all studied ligand interactions, a good correlation (with some few exceptions) between Loop C closure and the type of ligand (i.e., full and partial agonists, competitive antagonists, and modulators) was found [1]).

In addition to details on ligand interactions, AChBP studies have also helped in finding an ion selectivity filter in the extracellular domain of Cys-loop ligand-gated ion channels [59]. This selectivity filter is negatively charged in cation ion channels and positively charged in anion ion channels.

Concluding Remarks

AChRs mediate rapid transmission throughout the nervous system and also present functional roles in non-neuronal tissues. Structural and functional studies permitted to highlight the importance of the extracellular domain for the binding of agonists, competitive antagonists, and allosteric modulators. It is remarkable the advancement in our knowledge on ligand recognition and binding through the study of AChBPs from mollusks and annelids bound to a variety of ligands at atomic resolution. The current knowledge of the structural components of the AChR binding sites is paramount in differentiating agonists (full vs. partial) from competitive antagonists (small and large) and modulators. The crystallographic results in combination with mutagenesis, biochemical, electrophysiological, and animal behavior studies will help in the design of more selective agonists and competitive antagonists that can be used for the treatment of AChR-related diseases. For example, compound 5 (3-[(2(S)- azetidinyl)methoxy]-5-[(1S,2R)-2-(2-hydroxyethyl)cyclopropyl] pyridine) is a highly selective partial agonist of the a4ß2 AChR with anti depressant properties that has been recently co-crystallized with an AChBP [60-66].


I would like to thank Katarzyna Targowska-Duda (Medical University of Lublin, Poland) for super imposing the open and closed Torpedo AChR models.


Citation: Arias HR (2012) Molecular Interactions between Ligands and Nicotinic Acetylcholine Receptors Revealed by Studies with Acetylcholine Binding Proteins. J Thermodynam Cat 3: 116. Doi: 10.4172/2157-7544.1000116

Copyright: © 2012 Arias HR. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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