Biochimica et Biophysica Acta (BBA) - Reviews on Biomembranes最新文献

{"title":"Binding sites for exogenous and endogenous non-competitive inhibitors of the nicotinic acetylcholine receptor","authors":"Hugo Rubén Arias","doi":"10.1016/S0304-4157(98)00004-5","DOIUrl":"10.1016/S0304-4157(98)00004-5","url":null,"abstract":"<div><p><span>The nicotinic acetylcholine<span><span> receptor (AChR) is the paradigm of the neurotransmitter-gated ion channel superfamily. The pharmacological behavior of the AChR<span> 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 </span></span>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</span></span>⁺<span>), 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</span>⁺<span><span>, QX-222, cembranoids, and PCP bind to the serine, the </span>threonine<span><span>, and the leucine ring, whereas TID and meproadifen bind to the </span>valine<span> 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 Å from the lipid–water interface and ethidium binds to the vestibule of the AChR in a site located ∼46 Å 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<span>. 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 acco","PeriodicalId":100168,"journal":{"name":"Biochimica et Biophysica Acta (BBA) - Reviews on Biomembranes","volume":"1376 2","pages":"Pages 173-220"},"PeriodicalIF":0.0,"publicationDate":"1998-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0304-4157(98)00004-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20662391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}