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J. Biol. Chem., Vol. 282, Issue 47, 33949-33957, November 23, 2007

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Dual Effect of Acid pH on Purinergic P2X₃ Receptors Depends on the Histidine 206 Residue^*

Zoltan Gerevich¹, Zoltan S. Zadori, Laszlo Köles, Laurenz Kopp, Doreen Milius, Kerstin Wirkner, Klara Gyires, and Peter Illes

From the Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, D-04107 Leipzig, Germany and the Department of Pharmacology and Pharmacotherapy, Semmelweis University, H-1089 Budapest, Hungary

Whole cell patch clamp investigations were carried out to clarify the pH sensitivity of native and recombinant P2X₃ receptors. In HEK293 cells permanently transfected with human (h) P2X₃ receptors (HEK293-hP2X₃ cells), an acidic pH shifted the concentration-response curve for ,-methylene ATP (,-meATP) to the right and increased its maximum. An alkalic pH did not alter the effect of ,-meATP. Further, a low pH value increased the activation time constant (_on) of the ,-meATP current; the fast and slow time constants of desensitization (_des1, _des2) were at the same time also increased. Finally, acidification accelerated the recovery of P2X₃ receptors from the desensitized state. Replacement of histidine 206, but not histidine 45, by alanine abolished the pH-induced effects on hP2X₃ receptors transiently expressed in HEK293 cells. Changes in the intracellular pH had no effect on the amplitude or time course of the ,-meATP currents. The voltage sensitivity and reversal potential of the currents activated by ,-meATP were unaffected by extracellular acidification. Similar effects were observed in a subpopulation of rat dorsal root ganglion neurons expressing homomeric P2X₃ receptor channels. It is suggested that acidification may have a dual effect on P2X₃ channels, by decreasing the current amplitude at low agonist concentrations (because of a decrease in the rate of activation) and increasing it at high concentrations (because of a decrease in the rate of desensitization). Thereby, a differential regulation of pain sensation during e.g. inflammation may occur at the C fiber terminals of small DRG neurons in peripheral tissues.

Received for publication, July 16, 2007 , and in revised form, September 11, 2007.

^* This work was supported by the Deutsche Forschungsgemeinschaft (IL 20/11-3). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, Haertelstr. 16-18, D-04107 Leipzig, Germany. Tel.: 49-341-9724630; Fax: 49-341-9724609; E-mail: gerz{at}medizin.uni-leipzig.de.

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