title: A role for the Ca(2+)-dependent tyrosine kinase Pyk2 in tonic depolarization-induced vascular smooth muscle contraction.
abstract: Depolarization of the plasma membrane is a key mechanism of activation of contraction of vascular smooth muscle. This is commonly achieved in isolated, de-endothelialized vascular smooth muscle strips by increasing extracellular [K(+)] (replacing Na(+) by K(+)) and leads to a rapid phasic contraction followed by a sustained tonic contraction. The initial phasic contractile response is due to opening of voltage-gated Ca(2+) channels and entry of extracellular Ca(2+), which binds to calmodulin, leading to activation of myosin light chain kinase, phosphorylation of the regulatory light chains of myosin II at Ser19 and cross-bridge cycling. The subsequent tonic contractile response involves, in addition to myosin light chain kinase activation, Ca(2+)-induced Ca(2+) sensitization whereby Ca(2+) entry activates the RhoA/Rho-associated kinase pathway leading to phosphorylation of MYPT1 (the myosin targeting subunit of myosin light chain phosphatase) and inhibition of the phosphatase. Investigations into the mechanism of activation of RhoA by Ca(2+) have implicated a genistein-sensitive tyrosine kinase, and recent evidence indicates this to be the Ca(2+)-dependent tyrosine kinase, Pyk2.
authors.affiliation: Smooth Muscle Research Group and Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive N.W., Calgary, AB, T2N 4N1, Canada.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Mills
authors.affiliation: Department of Pharmacodynamics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo, 204-8588, Japan.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Mita
authors.affiliation: Smooth Muscle Research Group and Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive N.W., Calgary, AB, T2N 4N1, Canada. walsh@ucalgary.ca.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Walsh
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism*; D008564:Membrane Potentials / Q000502:physiology*; D009119:Muscle Contraction / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000502:physiology*; D018994:Myosin Light Chains / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D018994:Myosin Light Chains; D051418:Focal Adhesion Kinase 2; D054460:rho-Associated Kinases; D002118:Calcium
keywords: Calcium sensitization; Contractile regulation; Membrane depolarization; Pyk2; Tyrosine phosphorylation; Vascular smooth muscle