AMP-activated protein kinase phosphorylates and desensitizes smooth muscle myosin light chain kinase.
(2008) Journal of Biological Chemistry — Vol. 283, n° 27, p. 18505-18512 (2008)
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- Smooth muscle contraction is initiated by a rise in intracellular calcium leading to activation of smooth muscle myosin light-chain kinase via calcium/calmodulin. Activated myosin light chain kinase then phosphorylates the regulatory myosin light chains, triggering cross-bridge cycling and contraction. Here we show that myosin light-chain kinase is a substrate of AMP-activated protein kinase. The phosphorylation site in chicken myosin light chain kinase was identified by mass spectrometry to be located in the calmodulin-binding domain at Ser815. Phosphorylation by AMP-activated protein kinase desensitized myosin light-chain kinase by increasing the concentration of calmodulin required for half-maximal activation. In primary cultures of rat aortic smooth muscle cells, vasoconstrictors activated AMP-activated protein kinase in a calcium-dependent manner via calmodulin-dependent protein kinase kinase beta, a known upstream kinase of AMP-activated protein kinase. Indeed, vasoconstrictor-induced AMP-activated protein kinase activation was abrogated by the STO-609 calmodulin-dependent protein kinase kinase beta inhibitor. Myosin light chain phosphorylation was increased under these conditions, suggesting that contraction would be potentiated by ablation of AMP-activated protein kinase. Indeed in aortic rings from mice in which a1, the major catalytic subunit isoform in arterial smooth muscle, had been deleted, KCl- or phenylephrine-induced contraction was increased. The findings suggest that AMP-activated protein kinase attenuates contraction by phosphorylating and inactivating myosin light chain kinase. This might contribute to reduced ATP turnover in the tonic phase of smooth muscle contraction.
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Horman, S., Morel, N., Vertommen, D., Hussain, N., Neumann, D., Beauloye, C., El Najjar, N., Forcet, C., Viollet, B., Walsh, M. P., Hue, L., & Rider, M. H. (2008). AMP-activated protein kinase phosphorylates and desensitizes smooth muscle myosin light chain kinase. Journal of Biological Chemistry, 283(27), 18505-18512. https://doi.org/10.1074/jbc.M802053200 (Original work published 2008)