Purinergic P2X2 Receptor Desensitization Depends on Coupling between Ectodomain and C-Terminal Domain

doi:10.1124/mol.62.5.1187

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Vol. 62, Issue 5, 1187-1197, November 2002

Purinergic P2X₂ Receptor Desensitization Depends on Coupling between Ectodomain and C-Terminal Domain

Mu-Lan He, Taka-aki Koshimizu,¹ Melanija Tomi $c'$ , and Stanko S. Stojilkovic

Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland

The wild-type P2X₂ purinergic receptor (P2X_2aR) and its splice form lacking the intracellular Val³⁷⁰-Gln⁴³⁸ C-terminal sequence (P2X_2bR) respond to ATP stimulation withcomparable EC₅₀ values and peak current/calcium responses butdesensitize in a receptor-specific manner. P2X_2aR desensitizesslowly and P2X_2bR desensitizes rapidly. We studied the effectsof different agonists, and of substituting the ectodomain, onthe pattern of calcium signaling by P2X_2aR and P2X_2bR. Both receptorsshowed similar EC₅₀ values (estimated from the peak calcium response)and IC₅₀ values (estimated from the rate of calcium signal desensitization)for agonists, in the order 2-MeS-ATP $<=$ ATP $<=$ ATP $gamma$ S < BzATP $alpha$ $beta$ -meATP,and the IC₅₀ values for agonists were shifted to the right comparedwith their EC₅₀ values. Furthermore, the ATP-induced receptor-subtypespecific pattern of desensitization was mimicked by high- butnot by low-efficacy agonists, suggesting a ligand-specific desensitizationpattern. To test this hypothesis, we generated chimeric P2X_2aRand P2X_2bR containing the Val⁶⁰-Phe³⁰¹ ectodomain sequence of P2X₃R and Val⁶¹-Phe³¹³ ectodomain sequence of P2X₇R instead the native Ile⁶⁶-Tyr³¹⁰ sequence. The mutated P2X_2a+X₃R and P2X_2b+X₃R exhibited comparableEC₅₀ values for ATP, BzATP, and $alpha$ $beta$ -meATP in the submicromolarconcentration range and desensitized in a receptor-specific andligand-nonspecific manner. On the other hand, the chimeric P2X₂+X₇Rexhibited decreased sensitivity for ATP and desensitized in areceptor-nonspecific manner. These results suggest that efficacyof agonists for the ligand-binding domain of P2X₂Rs reflects thestrength of desensitization controlled by their C-terminalstructures.

¹ Current address: Department of Molecular Cell Pharmacology, National Children's Medical Research Center, Tokyo,Japan.

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