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

Area of Science:

• Molecular pharmacology
• Ion channel physiology
• G protein-coupled receptor signaling

Background:

• Nucleotide stimulation of G(q)-coupled P2Y receptors activates an endogenous ion channel in Xenopus oocytes.
• The transient inward (T(in)) channel's properties are modulated by specific P2Y receptor expression.

Purpose of the Study:

• To investigate the role of P2Y receptor C-terminal domains in modulating ion channel function.
• To identify specific regions within P2Y receptors responsible for altering ion channel gating.

Main Methods:

• Expression of various human and rat P2Y receptors, muscarinic, and bradykinin receptors in Xenopus oocytes.
• Electrophysiological recordings to assess T(in) channel voltage dependence and inactivation gating.
• Site-directed mutagenesis and peptide analysis of receptor C-terminal domains.

Main Results:

• Expression of P2Y(1), P2Y(2), P2Y(6), P2Y(11), and skate P2Y receptors altered T(in) channel gating.
• P2Y(4), M(1)-muscarinic, and B(1)-bradykinin receptors did not affect T(in) channel properties.
• The C-terminal domain of P2Y receptors, particularly a conserved motif, is responsible for modulating T(in) channel voltage dependence and inactivation.

Conclusions:

• Specific P2Y receptors interact with endogenous ion channels via their C-terminal domains to modulate voltage sensitivity and inactivation gating.
• This mechanism of ion channel modulation by P2Y receptors may be relevant in native mammalian cells.