ATP-sensitive potassium channel traffic regulation by adenosine and protein kinase C.
ATP-sensitive potassium (K(ATP)) channels activate under metabolic stress to protect neurons and cardiac myocytes. However, excessive channel activation may cause arrhythmia in the heart and silence neurons in the brain. Here, we report that PKC-mediated downregulation of K(ATP) channel number, via dynamin-dependent channel internalization, can act as a brake mechanism to control K(ATP) activation. A dileucine motif in the pore-lining Kir6.2 subunit of K(ATP), but not the site of PKC phosphorylation for channel activation, is essential for PKC downregulation. Whereas K(ATP) activation results in a rapid shortening of the action potential duration (APD) in metabolically inhibited ventricular myocytes, adenosine receptor stimulation and consequent PKC-mediated K(ATP) channel internalization can act as a brake to lessen this APD shortening. Likewise, in hippocampal CA1 neurons under metabolic stress, PKC-mediated, dynamin-dependent K(ATP) channel internalization can also act as a brake to dampen the rapid decline of excitability due to K(ATP) activation.
Howard Hughes Medical Institute, Department of Physiology, University of California, San Francisco, San Francisco, CA 94143, USA.
Keli
K
Hu
Cindy Shen
CS
Huang
Yuh Nung
YN
Jan
Lily Yeh
LY
Jan
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000241:Adenosine / Q000378:metabolism* / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism* / Q000494:pharmacology; D020816:Amino Acid Motifs / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D019556:COS Cells / Q000187:drug effects / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology*; D034281:Dynamins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D009924:Organ Culture Techniques; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018047:Receptors, Purinergic P1 / Q000187:drug effects / Q000378:metabolism; D013312:Stress, Physiological / Q000378:metabolism; D014982:Xenopus laevis
D004791:Enzyme Inhibitors; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D018047:Receptors, Purinergic P1; D000255:Adenosine Triphosphate; D011493:Protein Kinase C; D034281:Dynamins; D000241:Adenosine