Modulation of the inwardly rectifying potassium channel IRK1 by the m1 muscarinic receptor.
Modulation of the inwardly rectifying potassium channel (IRK1) by the m1 muscarinic receptor was studied with the whole-cell patch-clamp recording technique with the use of a mammalian expression system. After transfection with IRK1 and m1 muscarinic receptor genes, tsA cells expressed a cesium-sensitive inwardly rectifying potassium conductance that was reduced on application of the muscarinic receptor agonist carbachol. This reduction was reversible on washout of carbachol and could be completely inhibited by the muscarinic receptor antagonist atropine. Conversely, stimulation of the m2 muscarinic receptor, when coexpressed with IRK1, resulted in no change in IRK1 current amplitude. Phorbol-12, 13-dibutyrate, an activator of protein kinase c (PKC), mimicked the effect of m1 muscarinic receptor stimulation by inhibiting the IRK1 conductance. Preincubation with staurosporine or the specific PKC inhibitor calphostin C, before application of carbachol, fully prevented the inhibition of IRK1 by m1 muscarinic receptor stimulation. Administration of 8-bromo-cAMP, an activator of protein kinase A, and thapsigargin, a stimulator of intracellular calcium release, had no effect on IRK1, suggesting that these second messengers were not involved in the m1 muscarinic receptor-induced response. Therefore, the data indicate that the m1 muscarinic receptor inhibits IRK1, presumably via stimulation of PKC. As IRK1 is widely distributed throughout the central nervous system, it is possible that such an action on IRK1 underlies the inhibitory effects of muscarinic receptor stimulation on inwardly rectifying potassium conductances observed in the brain.
Jones
S V
SV
Department of Psychiatry, University of Vermont College of Medicine, Burlington 05405, USA.
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D006801:Humans; D051379:Mice; D015221:Potassium Channels / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology; D011976:Receptors, Muscarinic / Q000502:physiology*; D013729:Terpenes / Q000494:pharmacology; D019284:Thapsigargin
D015221:Potassium Channels; D011976:Receptors, Muscarinic; D013729:Terpenes; D015124:8-Bromo Cyclic Adenosine Monophosphate; D019284:Thapsigargin; D011493:Protein Kinase C