Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Action Potentials / drug effects
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Action Potentials / physiology
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Adenosine / metabolism*
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Adenosine / pharmacology
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Adenosine Triphosphate / metabolism*
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Adenosine Triphosphate / pharmacology
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Amino Acid Motifs / drug effects
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Amino Acid Motifs / physiology
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Animals
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Animals, Newborn
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COS Cells / drug effects
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COS Cells / metabolism
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Cell Membrane / drug effects
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Cell Membrane / enzymology*
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Dynamins / metabolism
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Enzyme Inhibitors / pharmacology
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Female
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Myocytes, Cardiac / drug effects
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Myocytes, Cardiac / enzymology*
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Neurons / drug effects
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Neurons / enzymology*
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Oocytes / drug effects
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Oocytes / metabolism
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Organ Culture Techniques
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Potassium Channels / drug effects
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Potassium Channels / metabolism*
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Potassium Channels, Inwardly Rectifying / drug effects
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Potassium Channels, Inwardly Rectifying / metabolism
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase C / metabolism*
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Rats
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Rats, Sprague-Dawley
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Receptors, Purinergic P1 / drug effects
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Receptors, Purinergic P1 / metabolism
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Stress, Physiological / metabolism
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Xenopus laevis
Substances
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Enzyme Inhibitors
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Potassium Channels
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Potassium Channels, Inwardly Rectifying
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Receptors, Purinergic P1
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Adenosine Triphosphate
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Protein Kinase C
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Dynamins
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Adenosine