A role for the Ca2+-dependent tyrosine kinase Pyk2 in tonic depolarization-induced vascular smooth muscle contraction

Depolarization of the plasma membrane is a key mechanism of activation of contraction of vascular smooth muscle. This is commonly achieved in isolated, deendothelialized 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 Ca2+ channels and entry of extracellular Ca2+, 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, Ca2+-induced Ca2+ sensitization whereby Ca2+ 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 Ca2+ have implicated a genistein-sensitive tyrosine kinase, and recent evidence indicates this to be the Ca2+-dependent tyrosine kinase, Pyk2.