title: Plasticity of sarcolemmal KATP channel surface expression: relevance during ischemia and ischemic preconditioning.
abstract: Myocardial ischemia remains the primary cause of morbidity and mortality in the United States. Ischemic preconditioning (IPC) is a powerful form of endogenous protection against myocardial infarction. We studied alterations in KATP channels surface density as a potential mechanism of the protection of IPC. Using cardiac-specific knockout of Kir6.2 subunits, we demonstrated an essential role for sarcolemmal KATP channels in the infarct-limiting effect of IPC in the mouse heart. With biochemical membrane fractionation, we demonstrated that sarcolemmal KATP channel subunits are distributed both to the sarcolemma and intracellular endosomal compartments. Global ischemia causes a loss of sarcolemmal KATP channel subunit distribution and internalization to endosomal compartments. Ischemia-induced internalization of KATP channels was prevented by CaMKII inhibition. KATP channel subcellular redistribution was also observed with immunohistochemistry. Ischemic preconditioning before the index ischemia reduced not only the infarct size but also prevented KATP channel internalization. Furthermore, not only did adenosine mimic IPC by preventing infarct size, but it also prevented ischemia-induced KATP channel internalization via a PKC-mediated pathway. We show that preventing endocytosis with dynasore reduced both KATP channel internalization and strongly mitigated infarct development. Our data demonstrate that plasticity of KATP channel surface expression must be considered as a potentially important mechanism of the protective effects of IPC and adenosine.
authors.affiliation: Pediatrics.
authors.forename: Hua-Qian
authors.initials: HQ
authors.lastname: Yang
authors.affiliation: Pediatrics.
authors.forename: Monique N
authors.initials: MN
authors.lastname: Foster
authors.affiliation: Pediatrics.
authors.forename: Kundan
authors.initials: K
authors.lastname: Jana
authors.affiliation: Pediatrics.
authors.forename: Joanne
authors.initials: J
authors.lastname: Ho
authors.affiliation: Cell Biology.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rindler
authors.affiliation: Pediatrics, Physiology & Neuroscience, and Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York william.coetzee@med.nyu.edu.
authors.forename: William A
authors.identifier: 0000-0003-1522-8326
authors.initials: WA
authors.lastname: Coetzee
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D006835:Hydrazones / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial; D000067268:Isolated Heart Preparation; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D000099161:Kcnj11 Channel
chemical_list: D000241:Adenosine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D006835:Hydrazones; D024661:Potassium Channels, Inwardly Rectifying; D011493:Protein Kinase C; D047428:Protein Kinase Inhibitors; D000099161:Kcnj11 Channel; C511794:N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide
keywords: KATP channels; endocytic recycling; ischemia; ischemic preconditioning