Protein kinase A modulates PLC-dependent regulation and PIP2-sensitivity of K+ channels.
Neurotransmitter and hormone regulation of cellular function can result from a concomitant stimulation of different signaling pathways. Signaling cascades are strongly regulated during disease and are often targeted by commonly used drugs. Crosstalk of different signaling pathways can have profound effects on the regulation of cell excitability. Members of all the three main structural families of potassium channels: inward-rectifiers, voltage-gated and 2-P domain, have been shown to be regulated by direct phosphorylation and Gq-coupled receptor activation. Here we test members of each of the three families, Kir3.1/Kir3.4, KCNQ1/KCNE1 and TREK-1 channels, all of which have been shown to be regulated directly by phosphatidylinositol bisphosphate (PIP2). The three channels are inhibited by activation of Gq-coupled receptors and are differentially regulated by protein kinase A (PKA). We show that Gq-coupled receptor regulation can be physiologically modulated directly through specific channel phosphorylation sites. Our results suggest that PKA phosphorylation of these channels affects Gq-coupled receptor inhibition through modulation of the channel sensitivity to PIP2.
Lopes
Coeli M B
CM
Department of Medicine, Cardiovascular Research Institute, University of Rochester, Rochester, New York 14642, USA. Coeli_Lopes@URMC.Rochester.edu
Remon
Juan I
JI
Matavel
Alessandra
A
Sui
Jin Liang
JL
Keselman
Inna
I
Medei
Emiliano
E
Shen
Yuming
Y
Rosenhouse-Dantsker
Avia
A
Rohacs
Tibor
T
Logothetis
Diomedes E
DE
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005260:Female; D031541:Fluorescence Resonance Energy Transfer; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D007668:Kidney / Q000166:cytology; D018613:Microscopy, Confocal; D009865:Oocytes; D018408:Patch-Clamp Techniques; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism* / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D010738:Type C Phospholipases / Q000378:metabolism*; D014981:Xenopus
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D019269:Phosphatidylinositol 4,5-Diphosphate; D015221:Potassium Channels; D017868:Cyclic AMP-Dependent Protein Kinases; D010738:Type C Phospholipases; D000109:Acetylcholine; D013755:Tetradecanoylphorbol Acetate