AMP-activated protein kinase phosphorylation of endothelial NO synthase |
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Authors: | Chen Z P Mitchelhill K I Michell B J Stapleton D Rodriguez-Crespo I Witters L A Power D A Ortiz de Montellano P R Kemp B E |
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Institution: | St. Vincent's Institute of Medical Research, St. Vincent's Hospital, Fitzroy, Vic., Australia. |
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Abstract: | The AMP-activated protein kinase (AMPK) in rat skeletal and cardiac muscle is activated by vigorous exercise and ischaemic stress. Under these conditions AMPK phosphorylates and inhibits acetyl-coenzyme A carboxylase causing increased oxidation of fatty acids. Here we show that AMPK co-immunoprecipitates with cardiac endothelial NO synthase (eNOS) and phosphorylates Ser-1177 in the presence of Ca2+-calmodulin (CaM) to activate eNOS both in vitro and during ischaemia in rat hearts. In the absence of Ca2+-calmodulin, AMPK also phosphorylates eNOS at Thr-495 in the CaM-binding sequence, resulting in inhibition of eNOS activity but Thr-495 phosphorylation is unchanged during ischaemia. Phosphorylation of eNOS by the AMPK in endothelial cells and myocytes provides a further regulatory link between metabolic stress and cardiovascular function. |
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