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J Biol Chem, Vol. 274, Issue 53, 37651-37657, December 31, 1999

Contributions of the C-terminal Domain to the Control of P2X Receptor Desensitization^*

Taka-aki Koshimizu, Miharu Koshimizu, and Stanko S. Stojilkovic

From the Endocrinology and Reproduction Research Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892

The P2X purinergic receptor channels (P2XRs) differ among themselves with respect to the rates of desensitization during prolonged agonist stimulation. Here we studied the desensitization of recombinant channels by monitoring the changes in intracellular free Ca²⁺ concentration in cells stimulated with ATP, the native and common agonist for all P2XRs. The focus in our investigations was on the relevance of the P2XR C terminus in controlling receptor desensitization. When expressed in GT1 cells, the P2XRs desensitized with rates characteristic to each receptor subtype: P2X₁R = P2X₃R > P2X_2bR > P2X₄R > P2X_2aR > P2X₇R. A slow desensitizing pattern of P2X_2aR was mimicked partially by P2X₃R and fully by P2X₄R when the six-amino acid sequences of these channels located in the cytoplasmic C terminus were substituted with the corresponding arginine 371 to proline 376 sequence of P2X_2aR. Changing the total net charge in the six amino acids of P2X₄R to a more positive direction also slowed the receptor desensitization. On the other hand, substitution of arginine 371-proline 376 sequence of P2X_2aR with the corresponding sequences of P2X₁R, P2X₃R, and P2X₄R increased the rate of receptor desensitization. Furthermore, heterologous polymerization of wild-type P2X_2aR and mutant P2X₃R having the C-terminal six amino acids of P2X_2aR at its analogous position resulted in a functional channel whose desensitization was significantly delayed. These results suggest that composition of the C-terminal six-amino acid sequence and its electrostatic force influence the rate of receptor desensitization.

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^* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Section on Cellular Signaling, ERRB/NICHD, Bldg. 49, Rm. 6A-36, 49 Convent Dr., Bethesda, MD 20892-4510. Tel.: 301-496-1638; Fax: 301-594-7031; E-mail: stankos@helix.nih.gov.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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