Key Sites for P2X Receptor Function and Multimerization: Overview of Mutagenesis Studies on a Structural Basis

P2X receptors constitute a seven-member family (P2X1-7) of extracellular ATP-gated cation channels of widespread expression. Because P2X receptors have been implicated in neurological, inflammatory and cardiovascular diseases, they constitute promising drug targets. Since the first P2X cDNA sequence...

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Main Authors:	Hausmann, Ralf, Kless, Achim, Schmalzing, Günther
Format:	Online
Language:	English
Published:	Bentham Science Publishers 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4460280/

id	pubmed-4460280
recordtype	oai_dc
spelling	pubmed-44602802015-06-17 Key Sites for P2X Receptor Function and Multimerization: Overview of Mutagenesis Studies on a Structural Basis Hausmann, Ralf Kless, Achim Schmalzing, Günther Article P2X receptors constitute a seven-member family (P2X1-7) of extracellular ATP-gated cation channels of widespread expression. Because P2X receptors have been implicated in neurological, inflammatory and cardiovascular diseases, they constitute promising drug targets. Since the first P2X cDNA sequences became available in 1994, numerous site-directed mutagenesis studies have been conducted to disclose key sites of P2X receptor function and oligomerization. The publication of the 3-Å crystal structures of the zebrafish P2X4 (zfP2X4) receptor in the homotrimeric apo-closed and ATP-bound open states in 2009 and 2012, respectively, has ushered a new era by allowing for the interpretation of the wealth of molecular data in terms of specific three-dimensional models and by paving the way for designing more-decisive experiments. Thanks to these structures, the last five years have provided invaluable insight into our understanding of the structure and function of the P2X receptor class of ligandgated ion channels. In this review, we provide an overview of mutagenesis studies of the pre- and post-crystal structure eras that identified amino acid residues of key importance for ligand binding, channel gating, ion flow, formation of the pore and the channel gate, and desensitization. In addition, the sites that are involved in the trimerization of P2X receptors are reviewed based on mutagenesis studies and interface contacts that were predicted by the zfP2X4 crystal structures. Bentham Science Publishers 2015-03 2015-03 /pmc/articles/PMC4460280/ /pubmed/25439586 http://dx.doi.org/10.2174/0929867322666141128163215 Text en © 2015 Bentham Science Publishers http://creativecommons.org/licenses/by-nc/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Hausmann, Ralf Kless, Achim Schmalzing, Günther
spellingShingle	Hausmann, Ralf Kless, Achim Schmalzing, Günther Key Sites for P2X Receptor Function and Multimerization: Overview of Mutagenesis Studies on a Structural Basis
author_facet	Hausmann, Ralf Kless, Achim Schmalzing, Günther
author_sort	Hausmann, Ralf
title	Key Sites for P2X Receptor Function and Multimerization: Overview of Mutagenesis Studies on a Structural Basis
title_short	Key Sites for P2X Receptor Function and Multimerization: Overview of Mutagenesis Studies on a Structural Basis
title_full	Key Sites for P2X Receptor Function and Multimerization: Overview of Mutagenesis Studies on a Structural Basis
title_fullStr	Key Sites for P2X Receptor Function and Multimerization: Overview of Mutagenesis Studies on a Structural Basis
title_full_unstemmed	Key Sites for P2X Receptor Function and Multimerization: Overview of Mutagenesis Studies on a Structural Basis
title_sort	key sites for p2x receptor function and multimerization: overview of mutagenesis studies on a structural basis
description	P2X receptors constitute a seven-member family (P2X1-7) of extracellular ATP-gated cation channels of widespread expression. Because P2X receptors have been implicated in neurological, inflammatory and cardiovascular diseases, they constitute promising drug targets. Since the first P2X cDNA sequences became available in 1994, numerous site-directed mutagenesis studies have been conducted to disclose key sites of P2X receptor function and oligomerization. The publication of the 3-Å crystal structures of the zebrafish P2X4 (zfP2X4) receptor in the homotrimeric apo-closed and ATP-bound open states in 2009 and 2012, respectively, has ushered a new era by allowing for the interpretation of the wealth of molecular data in terms of specific three-dimensional models and by paving the way for designing more-decisive experiments. Thanks to these structures, the last five years have provided invaluable insight into our understanding of the structure and function of the P2X receptor class of ligandgated ion channels. In this review, we provide an overview of mutagenesis studies of the pre- and post-crystal structure eras that identified amino acid residues of key importance for ligand binding, channel gating, ion flow, formation of the pore and the channel gate, and desensitization. In addition, the sites that are involved in the trimerization of P2X receptors are reviewed based on mutagenesis studies and interface contacts that were predicted by the zfP2X4 crystal structures.
publisher	Bentham Science Publishers
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4460280/
_version_	1613233287536312320

Key Sites for P2X Receptor Function and Multimerization: Overview of Mutagenesis Studies on a Structural Basis

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