Binding sites for exogenous and endogenous non-competitive inhibitors of the nicotinic acetylcholine receptor

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The nicotinic acetylcholine receptor (AChR) is the paradigm of the neurotransmitter-gated ion channel superfamily. The pharmacological behavior of the AChR can be described as three basic processes that progress sequentially. First, the neurotransmitter acetylcholine (ACh) binds the receptor. Next, the intrinsically coupled ion channel opens upon ACh binding with subsequent ion flux activity. Finally, the AChR becomes desensitized, a process where the ion channel becomes closed in the prolonged presence of ACh. The existing equilibrium among these physiologically relevant processes can be perturbed by the pharmacological action of different drugs. In particular, non-competitive inhibitors (NCIs) inhibit the ion flux and enhance the desensitization rate of the AChR. The action of NCIs was studied using several drugs of exogenous origin. These include compounds such as chlorpromazine (CPZ), triphenylmethylphosphonium (TPMP+), the local anesthetics QX-222 and meproadifen, trifluoromethyl-iodophenyldiazirine (TID), phencyclidine (PCP), histrionicotoxin (HTX), quinacrine, and ethidium. In order to understand the mechanism by which NCIs exert their pharmacological properties several laboratories have studied the structural characteristics of their binding sites, including their respective locations on the receptor. One of the main objectives of this review is to discuss all available experimental evidence regarding the specific localization of the binding sites for exogenous NCIs. For example, it is known that the so-called luminal NCIs bind to a series of ring-forming amino acids in the ion channel. Particularly CPZ, TPMP+, QX-222, cembranoids, and PCP bind to the serine, the threonine, and the leucine ring, whereas TID and meproadifen bind to the valine and extracellular rings, respectively. On the other hand, quinacrine and ethidium, termed non-luminal NCIs, bind to sites outside the channel lumen. Specifically, quinacrine binds to a non-annular lipid domain located ~7 A from the lipid-water interface and ethidium binds to the vestibule of the AChR in a site located ~46 A away from the membrane surface and equidistant from both ACh binding sites. The non-annular lipid domain has been suggested to be located at the intermolecular interfaces of the five AChR subunits and/or at the interstices of the four (M1-M4) transmembrane domains. One of the most important concepts in neurochemistry is that receptor proteins can be modulated by endogenous substances other than their specific agonists. Among membrane-embedded receptors, the AChR is one of the best examples of this behavior. In this regard, the AChR is non-competitively modulated by diverse molecules such as lipids (fatty acids and steroids), the neuropeptide substance P, and the neurotransmitter 5-hydroxytryptamine (5-HT). It is important to take into account that the above mentioned modulation is produced through a direct binding of these endogenous molecules to the AChR. Since this is a physiologically relevant issue, it is useful to elucidate the structural components of the binding site for each endogenous NCI. In this regard, another important aim of this work is to review all available information related to the specific localization of the binding sites for endogenous NCIs. For example, it is known that both neurotransmitters substance P and 5-HT bind to the lumen of the ion channel. Particularly, the locus for substance P is found in the δM2 domain, whereas the binding site for 5-HT and related compounds is putatively located on both the serine and the threonine ring. Instead, fatty acid and steroid molecules bind to non-luminal sites. More specifically, fatty acids may bind to the belt surrounding the intramembranous perimeter of the AChR, namely the annular lipid domain, and/or to the high-affinity quinacrine site which is located at a non-annular lipid domain. Additionally, steroids may bind to a site located on the extracellular hydrophilic domain of the AChR and/or at the lipid-protein interface. Specifically, at the annular lipid domain or close to the non-annular quinacrine binding site. The self-inhibitory action of ACh at millimolar concentrations can be also considered an endogenous mechanism for the functional modulation of the AChR. Studies on the localization of the agonist self-inhibitory locus suggest that agonists at very high concentrations may bind to the ion channel (a luminal site) and/or to the quinacrine site (a non-luminal site). Focusing on the premise that certain structural domains of the AChR involved in NCI binding account for the functional effect of the ligand under study, the existence of luminal and non-luminal binding sites supports the idea of at least two distinct mechanisms of action for NCIs: a steric mechanism where the drug obstructs the ion permeation and an allosteric process where the AChR, upon ligand binding, suffers such a conformational change that the ion channel becomes closed and thus the ion flux is impeded. Copyright (C) 1998 Elsevier Science B.V.

Original languageEnglish
Pages (from-to)173-220
Number of pages48
JournalBiochimica et Biophysica Acta - Reviews on Biomembranes
Issue number2
StatePublished - 21 Aug 1998
Externally publishedYes


  • Agonist self-inhibitory binding site
  • Endogenous non-competitive inhibitor
  • Exogenous non-competitive inhibitor
  • Luminal non-competitive inhibitor binding site
  • Nicotinic acetylcholine receptor
  • Non-luminal non-competitive inhibitor binding site

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