Two-pore potassium ion channels are inhibited by both G(q/11)- and G(i)-coupled P2Y receptors

Molecular and Cellular Neurosciences
Sony Shakya ShresthaTrevor J Bushell

Abstract

Two-pore potassium (K(2P)) ion channels and P2Y receptors modulate the activity of neurones and are targets for the treatment of neuronal disorders. Here we have characterised their interaction. In cells coexpressing the Galpha(i)-coupled hP2Y(12) receptor, ADP and ATP significantly inhibited hK(2P)2.1 currents. This was abolished by pertussis toxin (PTX), the hP2Y(12) antagonist AR-C69931MX, the hP2Y(1) antagonist MRS2179 and by mutating potential PKA/PKC phosphorylation sites in the channel C terminal. In cells coexpressing the Galpha(q/11)-coupled hP2Y(1) receptor, ADP and ATP also inhibited hK(2P)2.1 currents, which were abolished by MRS2179, but unaffected by AR-C69931MX and PTX. When both receptors were coexpressed with K(2P)2.1 channels, ADP-induced inhibition was antagonised by AR-C69913MX and MRS2179, but not PTX. Thus, both Galpha(q/11)- and Galpha(i)-coupled P2Y receptors inhibit K(2P) channels and the action of hP2Y(12) receptors appears to involve co-activation of endogenous hP2Y(1) receptors. This represents a novel mechanism by which P2Y receptors may modulate neuronal activity.

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Citations

Nov 1, 2012·Wiley Interdisciplinary Reviews. Membrane Transport and Signaling·Laurie Erb, Gary A Weisman
Dec 7, 2020·Biochemical Pharmacology·Vera Ralevic
Feb 24, 2021·Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society·Sara TraserraMarcel Jimenez
Dec 15, 2020·Biochemical Pharmacology·Ivar von Kügelgen

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