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J. Biol. Chem., Vol. 277, Issue 49, 46891-46899, December 6, 2002

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Heteromultimerization Modulates P2X Receptor Functions through Participating Extracellular and C-terminal Subdomains^*

Taka-aki Koshimizu^§, Susumu Ueno^¶, Akito Tanoue, Nobuyuki Yanagihara^¶, Stanko S. Stojilkovic, and Gozoh Tsujimoto^**

From the  Department of Molecular and Cell Pharmacology,  Endocrinology and Reproduction Research Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892 and the ^¶ Department of Pharmacology, University of Occupational and Environmental Health, Japan School of Medicine, Tokyo 154-8567, Japan

P2X purinergic receptors (P2XRs) differ among themselves with respect to their ligand preferences and channel kinetics during activation, desensitization, and recovery. However, the contributions of distinct receptor subdomains to the subtype-specific behavior have been incompletely characterized. Here we show that homomeric receptors having the extracellular domain of the P2X₃ subunit in the P2X_2a-based backbone (P2X_2a/X₃ex) mimicked two intrinsic functions of P2X₃R, sensitivity to -methylene ATP and ecto-ATPase-dependent recovery from endogenous desensitization; these two functions were localized to the N- and C-terminal halves of the P2X₃ extracellular loop, respectively. The chimeric P2X_2aR/X₃ex receptors also desensitized with accelerated rates compared with native P2X_2aR, and the introduction of P2X₂ C-terminal splicing into the chimeric subunit (P2X_2b/X₃ex) further increased the rate of desensitization. Physical and functional heteromerization of native P2X_2a and P2X_2b subunits was also demonstrated. In heteromeric receptors, the ectodomain of P2X₃ was a structural determinant for ligand selectivity and recovery from desensitization, and the C terminus of P2X₂ was an important factor for the desensitization rate. Furthermore, [-³²P]8-azido ATP, a photoreactive agonist, was effectively cross-linked to P2X₃ subunit in homomeric receptors but not in heteromeric P2X₂ + P2X₃Rs. These results indicate that heteromeric receptors formed by distinct P2XR subunits develop new functions resulting from integrative effects of the participating extracellular and C-terminal subdomains.

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