Molecular basis of protein kinase C-induced activation of ATP-sensitive potassium channels.
Potassium channels that are inhibited by internal ATP (K(ATP) channels) provide a critical link between metabolism and cellular excitability. Protein kinase C (PKC) acts on K(ATP) channels to regulate diverse cellular processes, including cardioprotection by ischemic preconditioning and pancreatic insulin secretion. PKC action decreases the Hill coefficient of ATP binding to cardiac K(ATP) channels, thereby increasing their open probability at physiological ATP concentrations. We show that PKC similarly regulates recombinant channels from both the pancreas and heart. Surprisingly, PKC acts via phosphorylation of a specific, conserved threonine residue (T180) in the pore-forming subunit (Kir6.2). Additional PKC consensus sites exist on both Kir and the larger sulfonylurea receptor (SUR) subunits. Nonetheless, T180 controls changes in open probability induced by direct PKC action either in the absence of, or in complex with, the accessory SUR1 (pancreatic) or SUR2A (cardiac) subunits. The high degree of conservation of this site among different K(ATP) channel isoforms suggests that this pathway may have wide significance for the physiological regulation of K(ATP) channels in various tissues and organelles.
Light
P E
PE
Departments of Physiology and Biophysics, Pharmacology and Therapeutics, and Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada T2N 4N1. peter.light@ualberta.ca
Bladen
C
C
Winkfein
R J
RJ
Walsh
M P
MP
French
R J
RJ
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002461:Cell Line, Transformed; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D015221:Potassium Channels / Q000737:chemistry / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying; D011493:Protein Kinase C / Q000378:metabolism*; D011817:Rabbits
D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D000255:Adenosine Triphosphate; D011493:Protein Kinase C