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J. Biol. Chem., Vol. 283, Issue 8, 5110-5117, February 22, 2008

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On the Role of the First Transmembrane Domain in Cation Permeability and Flux of the ATP-gated P2X₂ Receptor^*

From the Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri 63104

P2X receptors are a family of seven ligand-gated ion channels (P2X₁-P2X₇) that open in the presence of ATP. We used alanine-scanning mutagenesis and patch clamp photometry to study the role of the first transmembrane domain of the rat P2X₂ receptor in cation permeability and flux. Three alanine-substituted mutants did not respond to ATP, and 19 of the 22 functional receptors resembled the wild-type receptor with regard to the fraction of the total ATP-gated current carried by calcium or the permeability of calcium relative to cesium. The remaining three mutants showed modest changes in calcium dynamics. Two of these occurred at sites (Gly³⁰ and Phe⁴⁴) that are unlikely to interact with permeating cations in a meaningful way. The third was a conserved tyrosine (Tyr⁴³) that may form an inter-pore binding site for calcium. The data suggest that, with the possible exception of Tyr⁴³, the first transmembrane domain contributes little to the permeation properties of the P2X₂ receptor.

Received for publication, October 22, 2007 , and in revised form, November 27, 2007.

^* This work was supported by grants from the National Institutes of Health. 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 Present address: Dept. of Brain Neurophysiology, Hirosaki University Graduate School of Medicine, 5 Zaifutyo, Hirosaki City, Aomori 036-8562, Japan.

² To whom correspondence should be addressed: Dept. of Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 S. Grand Blvd., St. Louis, MO 63104. Tel.: 314-977-6429; Fax: 314-977-6411; E-mail: egantm{at}slu.edu.

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