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The structural basis of function in Cys-loop receptors

Thompson, Andrew J. and Lester, Henry A. and Lummis, Sarah C. R. (2010) The structural basis of function in Cys-loop receptors. Quarterly Reviews of Biophysics, 43 (4). pp. 449-499. ISSN 0033-5835. doi:10.1017/S0033583510000168. https://resolver.caltech.edu/CaltechAUTHORS:20101221-093346658

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Abstract

Cys-loop receptors are membrane-spanning neurotransmitter-gated ion channels that are responsible for fast excitatory and inhibitory transmission in the peripheral and central nervous systems. The best studied members of the Cys-loop family are nACh, 5-HT_3, GABA_A and glycine receptors. All these receptors share a common structure of five subunits, pseudo-symmetrically arranged to form a rosette with a central ion-conducting pore. Some are cation selective (e.g. nACh and 5-HT_3) and some are anion selective (e.g. GABA_A and glycine). Each receptor has an extracellular domain (ECD) that contains the ligand-binding sites, a transmembrane domain (TMD) that allows ions to pass across the membrane, and an intracellular domain (ICD) that plays a role in channel conductance and receptor modulation. Cys-loop receptors are the targets for many currently used clinically relevant drugs (e.g. benzodiazepines and anaesthetics). Understanding the molecular mechanisms of these receptors could therefore provide the catalyst for further development in this field, as well as promoting the development of experimental techniques for other areas of neuroscience. In this review, we present our current understanding of Cys-loop receptor structure and function. The ECD has been extensively studied. Research in this area has been stimulated in recent years by the publication of high-resolution structures of nACh receptors and related proteins, which have permitted the creation of many Cys loop receptor homology models of this region. Here, using the 5-HT_3 receptor as a typical member of the family, we describe how homology modelling and ligand docking can provide useful but not definitive information about ligand interactions. We briefly consider some of the many Cys-loop receptors modulators. We discuss the current understanding of the structure of the TMD, and how this links to the ECD to allow channel gating, and consider the roles of the ICD, whose structure is poorly understood. We also describe some of the current methods that are beginning to reveal the differences between different receptor states, and may ultimately show structural details of transitions between them.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1017/S0033583510000168 DOIArticle
http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=7926517PublisherArticle
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Lummis, Sarah C. R.0000-0001-9410-9805
Additional Information:© 2010 Cambridge University Press. Published online: 20 Sep 2010. The authors’ research is supported by the Wellcome Trust (SCRL, AJT; SCRL is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science) ; the EU (SCRL; NeuroCypres FP7) and NIH (HAL).
Funders:
Funding AgencyGrant Number
Wellcome TrustUNSPECIFIED
European Union (EU)NeuroCypres
NIHUNSPECIFIED
Issue or Number:4
DOI:10.1017/S0033583510000168
Record Number:CaltechAUTHORS:20101221-093346658
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20101221-093346658
Official Citation:Thompson, A. J., H. A. Lester, et al. (2010). "The structural basis of function in Cys-loop receptors." Quarterly Reviews of Biophysics 43(04): 449-499.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:21473
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:12 Jan 2011 18:57
Last Modified:09 Nov 2021 15:57

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