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Metabotropic P2Y receptors inhibit P2X3 receptor-channels via G protein-dependent facilitation of their desensitization.
Br J Pharmacol. 2007 May; 151(2):226-36.BJ

Abstract

BACKGROUND AND PURPOSE

The aim of the present study was to investigate whether the endogenous metabotropic P2Y receptors modulate ionotropic P2X(3) receptor-channels.

EXPERIMENTAL APPROACH

Whole-cell patch-clamp experiments were carried out on HEK293 cells permanently transfected with human P2X(3) receptors (HEK293-hP2X(3) cells) and rat dorsal root ganglion (DRG) neurons.

KEY RESULTS

In both cell types, the P2Y(1,12,13) receptor agonist, ADP-beta-S, inhibited P2X(3) currents evoked by the selective agonist, alpha,beta-methylene ATP (alpha,beta-meATP). This inhibition could be markedly counteracted by replacing in the pipette solution the usual GTP with GDP-beta-S, a procedure known to block all G protein heterotrimers. P2X(3) currents evoked by ATP, activating both P2Y and P2X receptors, caused a smaller peak amplitude and desensitized faster than those currents evoked by the selective P2X(3) receptor agonist alpha,beta-meATP. In the presence of intracellular GDP-beta-S, ATP- and alpha,beta-meATP-induced currents were identical. Recovery from P2X(3) receptor desensitization induced by repetitive ATP application was slower than the recovery from alpha,beta-meATP-induced desensitization. When G proteins were blocked by intracellular GDP-beta-S, the recovery from the ATP- and alpha,beta-meATP-induced desensitization were of comparable speed.

CONCLUSIONS AND IMPLICATIONS

Our results suggest that the activation of P2Y receptors G protein-dependently facilitates the desensitization of P2X(3) receptors and suppresses the recovery from the desensitized state. Hence, the concomitant stimulation of P2X(3) and P2Y receptors of DRG neurons by ATP may result both in an algesic effect and a partly counterbalancing analgesic activity.

Authors+Show Affiliations

Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, Leipzig, Germany. Gerz@medizin.uni-leipzig.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17351651

Citation

Gerevich, Z, et al. "Metabotropic P2Y Receptors Inhibit P2X3 Receptor-channels Via G Protein-dependent Facilitation of Their Desensitization." British Journal of Pharmacology, vol. 151, no. 2, 2007, pp. 226-36.
Gerevich Z, Zadori Z, Müller C, et al. Metabotropic P2Y receptors inhibit P2X3 receptor-channels via G protein-dependent facilitation of their desensitization. Br J Pharmacol. 2007;151(2):226-36.
Gerevich, Z., Zadori, Z., Müller, C., Wirkner, K., Schröder, W., Rubini, P., & Illes, P. (2007). Metabotropic P2Y receptors inhibit P2X3 receptor-channels via G protein-dependent facilitation of their desensitization. British Journal of Pharmacology, 151(2), 226-36.
Gerevich Z, et al. Metabotropic P2Y Receptors Inhibit P2X3 Receptor-channels Via G Protein-dependent Facilitation of Their Desensitization. Br J Pharmacol. 2007;151(2):226-36. PubMed PMID: 17351651.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Metabotropic P2Y receptors inhibit P2X3 receptor-channels via G protein-dependent facilitation of their desensitization. AU - Gerevich,Z, AU - Zadori,Z, AU - Müller,C, AU - Wirkner,K, AU - Schröder,W, AU - Rubini,P, AU - Illes,P, Y1 - 2007/03/12/ PY - 2007/3/14/pubmed PY - 2007/8/8/medline PY - 2007/3/14/entrez SP - 226 EP - 36 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 151 IS - 2 N2 - BACKGROUND AND PURPOSE: The aim of the present study was to investigate whether the endogenous metabotropic P2Y receptors modulate ionotropic P2X(3) receptor-channels. EXPERIMENTAL APPROACH: Whole-cell patch-clamp experiments were carried out on HEK293 cells permanently transfected with human P2X(3) receptors (HEK293-hP2X(3) cells) and rat dorsal root ganglion (DRG) neurons. KEY RESULTS: In both cell types, the P2Y(1,12,13) receptor agonist, ADP-beta-S, inhibited P2X(3) currents evoked by the selective agonist, alpha,beta-methylene ATP (alpha,beta-meATP). This inhibition could be markedly counteracted by replacing in the pipette solution the usual GTP with GDP-beta-S, a procedure known to block all G protein heterotrimers. P2X(3) currents evoked by ATP, activating both P2Y and P2X receptors, caused a smaller peak amplitude and desensitized faster than those currents evoked by the selective P2X(3) receptor agonist alpha,beta-meATP. In the presence of intracellular GDP-beta-S, ATP- and alpha,beta-meATP-induced currents were identical. Recovery from P2X(3) receptor desensitization induced by repetitive ATP application was slower than the recovery from alpha,beta-meATP-induced desensitization. When G proteins were blocked by intracellular GDP-beta-S, the recovery from the ATP- and alpha,beta-meATP-induced desensitization were of comparable speed. CONCLUSIONS AND IMPLICATIONS: Our results suggest that the activation of P2Y receptors G protein-dependently facilitates the desensitization of P2X(3) receptors and suppresses the recovery from the desensitized state. Hence, the concomitant stimulation of P2X(3) and P2Y receptors of DRG neurons by ATP may result both in an algesic effect and a partly counterbalancing analgesic activity. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/17351651/Metabotropic_P2Y_receptors_inhibit_P2X3_receptor_channels_via_G_protein_dependent_facilitation_of_their_desensitization_ L2 - https://doi.org/10.1038/sj.bjp.0707217 DB - PRIME DP - Unbound Medicine ER -