Vol. 63, Issue 4, 878-885, April 2003

P2Y Receptors Modulate Ion Channel Function through Interactions Involving The C-Terminal Domain

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

Department of Physiology and Molecular Veterinary Biosciences Graduate Program (S.Y.L.) and Departments of Physiology and Animal Science (S.M.O.), University of Minnesota, St. Paul, Minnesota; and Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina (S.C.W., R.A.N.)

Nucleotide stimulation of G_q-coupled P2Y receptors expressed in Xenopus laevis oocytes produces the activation of an endogenous voltage-gated ion channel, previously identified as the transient inward (T_in) 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 T_in 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 T_in 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 T_in channel. This region contains a conserved sequence motif found in all P2Y receptors that modulates the voltage dependence of the T_in 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.