Amino acid residues in the P2X7 receptor that mediate differential sensitivity to ATP and BzATP

Young, Mark T.; Pelegrin, Pablo; Surprenant, Annmarie

Publication:
Amino acid residues in the P2X7 receptor that mediate differential sensitivity to ATP and BzATP

dc.contributor.author	Young, Mark T.
dc.contributor.author	Pelegrin, Pablo
dc.contributor.author	Surprenant, Annmarie
dc.contributor.department	Bioquímica y Biología Molecular B e Inmunología
dc.date.accessioned	2024-01-30T11:11:34Z
dc.date.available	2024-01-30T11:11:34Z
dc.date.issued	2007
dc.description	©2007. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ This document is the Accepted, version of a Published Work that appeared in final form in Molecular Pharmacology,. To access the final edited and published work see https://doi.org10.1124/mol.106.030163
dc.description.abstract	Agonist properties of the P2X7 receptor (P2X7R) differ strikingly from other P2X receptors in two main ways: high concentrations of ATP (> 100 microM) are required to activate the receptor, and the ATP analog 2',3'-O-(4-benzoyl-benzoyl)ATP (BzATP) is both more potent than ATP and evokes a higher maximum current. However, there are striking species differences in these properties. We sought to exploit the large differences in ATP and BzATP responses between rat and mouse P2X7R to delineate regions or specific residues that may be responsible for the unique actions of these agonists at the P2X7R. We measured membrane currents in response to ATP and BzATP at wild-type rat and mouse P2X7R, at chimeric P2X7Rs, and at mouse P2X7Rs bearing point mutations. Wild-type rat P2X7R was 10 times more sensitive to ATP and 100 times more sensitive to BzATP than wild-type mouse P2X7R. We found that agonist EC50 values were determined solely by the ectodomain of the P2X7R. Two segments (residues 115-136 and 282-288), when transposed together, converted mouse sensitivities to those of rat. Point mutations through these regions revealed a single residue, asparagine284, in the rat P2X7R that fully accounted for the 10-fold difference in ATP sensitivity, whereas the 100-fold difference in BzATP sensitivity required the transfer of both Lys127 and Asn284 from rat to mouse. Thus, single amino acid differences between species can account for large changes in agonist effectiveness and differentiate between the two widely used agonists at P2X7 receptors.	es
dc.format	application/pdf	es
dc.format.extent	25	es
dc.identifier.doi	https://doi.org10.1124/mol.106.030163
dc.identifier.eisbn	Molecular Pharmacology, volumen 71, nº 1, año 2007, páginas: 92-100.	es
dc.identifier.uri	http://hdl.handle.net/10201/138129
dc.language	eng	es
dc.publisher	American Society for Pharmacology and Experimental Therapeutics	es
dc.relation	Wellcome Trust, Biotechnology and Biological Sciences Research Council.	es
dc.relation.publisherversion	https://molpharm.aspetjournals.org/content/71/1/92.long	es
dc.rights	info:eu-repo/semantics/openAccess	es
dc.rights	Attribution-NonCommercial-NoDerivatives 4.0 Internacional	*
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/4.0/	*
dc.subject	P2X7	es
dc.subject	ATP	es
dc.subject	Canal iónico	es
dc.subject.other	CDU::6 - Ciencias aplicadas	es
dc.title	Amino acid residues in the P2X7 receptor that mediate differential sensitivity to ATP and BzATP	es
dc.title.alternative	Different sites for ATP and BzATP at P2X7 receptors	es
dc.type	info:eu-repo/semantics/article	es
dspace.entity.type	Publication	es