Document Detail

Topology of ligand binding sites on the nicotinic acetylcholine receptor.
MedLine Citation:
PMID:  9403137     Owner:  NLM     Status:  MEDLINE    
The nicotinic acetylcholine receptor (AChR) presents two very well differentiated domains for ligand binding that account for different cholinergic properties. In the hydrophilic extracellular region of both alpha subunits there exist the binding sites for agonists such as the neurotransmitter acetylcholine (ACh) and for competitive antagonists such as d-tubocurarine. Agonists trigger the channel opening upon binding while competitive antagonists compete for the former ones and inhibit its pharmacological action. Identification of all residues involved in recognition and binding of agonist and competitive antagonists is a primary objective in order to understand which structural components are related to the physiological function of the AChR. The picture for the localisation of the agonist/competitive antagonist binding sites is now clearer in the light of newer and better experimental evidence. These sites are mainly located on both alpha subunits in a pocket approximately 30-35 A above the surface membrane. Since both alpha subunits are sequentially identical, the observed high and low affinity for agonists on the receptor is conditioned by the interaction of the alpha subunit with the delta or the gamma chain, respectively. This relationship is opposite for curare-related drugs. This molecular interaction takes place probably at the interface formed by the different subunits. The principal component for the agonist/competitive antagonist binding sites involves several aromatic residues, in addition to the cysteine pair at 192-193, in three loops-forming binding domains (loops A-C). Other residues such as the negatively changed aspartates and glutamates (loop D), Thr or Tyr (loop E), and Trp (loop F) from non-alpha subunits were also found to form the complementary component of the agonist/competitive antagonist binding sites. Neurotoxins such as alpha-, kappa-bungarotoxin and several alpha-conotoxins seem to partially overlap with the agonist/competitive antagonist binding sites at multiple point of contacts. The alpha subunits also carry the binding site for certain acetylcholinesterase inhibitors such as eserine and for the neurotransmitter 5-hydroxytryptamine which activate the receptor without interacting with the classical agonist binding sites. The link between specific subunits by means of the binding of ACh molecules might play a pivotal role in the relative shift among receptor subunits. This conformational change would allow for the opening of the intrinsic receptor cation channel transducting the external chemical signal elicited by the agonist into membrane depolarisation. The ion flux activity can be inhibited by non-competitive inhibitors (NCIs). For this kind of drugs, a population of low-affinity binding sites has been found at the lipid-protein interface of the AChR. In addition, several high-affinity binding sites have been found to be located at different rings on the M2 transmembrane domain, namely luminal binding sites. In this regard, the serine ring is the locus for exogenous NCIs such as chlorpromazine, triphenylmethylphosphonium, the local anaesthetic QX-222, phencyclidine, and trifluoromethyliodophenyldiazirine. Trifluoromethyliodophenyldiazirine also binds to the valine ring, which is the postulated site for cembranoids. Additionally, the local anaesthetic meproadifen binding site seems to be located at the outer or extracellular ring. Interestingly, the M2 domain is also the locus for endogenous NCIs such as the neuropeptide substance P and the neurotransmitter 5-hydroxytryptamine. In contrast with this fact, experimental evidence supports the hypothesis for the existence of other NCI high-affinity binding sites located not at the channel lumen but at non-luminal binding domains. (ABSTRACT TRUNCATED)
H R Arias
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Brain research. Brain research reviews     Volume:  25     ISSN:  -     ISO Abbreviation:  Brain Res. Brain Res. Rev.     Publication Date:  1997 Oct 
Date Detail:
Created Date:  1998-01-15     Completed Date:  1998-01-15     Revised Date:  2007-02-26    
Medline Journal Info:
Nlm Unique ID:  8908638     Medline TA:  Brain Res Brain Res Rev     Country:  NETHERLANDS    
Other Details:
Languages:  eng     Pagination:  133-91     Citation Subset:  IM    
Instituto de Investigaciones Bioquímicas de Bahía Blanca, Consejo Nacional de Investigaciones Científicas y Técnicas, Bahía Blanca, Argentina.
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MeSH Terms
Acetylcholine / metabolism
Binding Sites
Cholinesterase Inhibitors / pharmacology
Macromolecular Substances
Models, Molecular
Muscles / metabolism
Neurons / metabolism
Nicotinic Agonists / metabolism
Nicotinic Antagonists / metabolism,  pharmacology
Protein Conformation
Receptors, Nicotinic / chemistry*,  metabolism*
Tubocurarine / metabolism
Reg. No./Substance:
0/Cholinesterase Inhibitors; 0/Ligands; 0/Macromolecular Substances; 0/Nicotinic Agonists; 0/Nicotinic Antagonists; 0/Receptors, Nicotinic; 51-84-3/Acetylcholine; 57-95-4/Tubocurarine

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