title: Two-pore potassium ion channels are inhibited by both G(q/11)- and G(i)-coupled P2Y receptors.
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.
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, John Arbuthnott Building, 27 Taylor Street, Glasgow G4 ONR, UK.
authors.forename: Sony Shakya
authors.initials: SS
authors.lastname: Shrestha
authors.forename: Miralkumar
authors.initials: M
authors.lastname: Parmar
authors.forename: Charles
authors.initials: C
authors.lastname: Kennedy
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Bushell
mesh_terms: D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000249:Adenosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000704:Analysis of Variance; D002460:Cell Line; D002478:Cells, Cultured; D004594:Electrophysiology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D024683:Potassium Channels, Tandem Pore Domain / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000378:metabolism*
chemical_list: C111914:N(6)-methyl-2'-deoxyadenosine 3',5'-diphosphate; D024683:Potassium Channels, Tandem Pore Domain; D018048:Receptors, Purinergic P2; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; C117446:cangrelor