P2Y receptors modulate ion channel function through interactions involving the C-terminal domain

So Yeong Lee, Samuel C. Wolff, Robert A. Nicholas, Scott M. O'Grady

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Nucleotide stimulation of Gq-coupled P2Y receptors expressed in Xenopus laevis oocytes produces the activation of an endogenous voltage-gated ion channel, previously identified as the transient inward (Tin) channel. Expression of human P2Y1, human P2Y2, rat P2Y6, human P2Y11, or skate P2Y receptors in oocytes resulted in modulation of the voltage dependence and inactivation gating of the channel. Expression of the human P2Y4 receptor, rat M1-muscarinic receptor, and human B1-bradykinin receptor did not alter the properties of the Tin channel. Replacement of the C-terminal domain of the human B1-bradykinin receptor with the C-terminal domains of either the human P2Y1 or human P2Y2 receptor resulted in voltage dependence and inactivation-gating properties, respectively, of the Tin channel that were similar to those elicited by the respective native P2Y receptor. Systematic truncation of the C-terminal region of the human P2Y1 receptor identified a short region responsible for modulation of the Tin channel. This region contains a conserved sequence motif found in all P2Y receptors that modulates the voltage dependence of the Tin channel. Synthetic 20-mer peptides from the C-terminal domains of human P2Y1 and P2Y2 receptors produced a shift in the voltage dependence and slowed inactivation gating, respectively, after injection into oocytes expressing human B1-bradykinin or truncated human P2Y1 receptors. These results indicate that certain P2Y receptors are capable of modulating the voltage sensitivity and inactivation gating of an endogenous oocyte ion channel through interactions involving the C-terminal region of the receptor. Such modulation of ion channel function could also exist in native mammalian cells that express P2Y receptors.

Original languageEnglish (US)
Pages (from-to)878-885
Number of pages8
JournalMolecular Pharmacology
Volume63
Issue number4
DOIs
StatePublished - Apr 1 2003

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