A role for the Ca2+-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.

A role for focal adhesion kinase in facilitating the contractile responses of murine gastric fundus smooth muscles

“…Thus, whether the decrease in MYPT1 T696 and T853 phosphorylation by PF‐431396 is due to inhibition of FAK activation upstream of the RhoA/ROCK pathway, as reported for caudal arteries, is unclear (Mills et al . ).…”

“…; Mills et al . ). The present work introduces an additional role for FAK in gastric fundus smooth muscle contractile function, by an apparent involvement in the regulation of CPI‐17 and also MYPT1 phosphorylation.…”

“…; Mills et al . ). This remodelling process is thought to facilitate the polymerization of cortical cytoskeletal actin filaments to increase the stability of focal adhesions in the membrane, allowing for the force generated by myofilament activation to be transmitted to the connective tissue of the extracellular matrix (Mehta & Gunst, ; Chen et al .…”

STIM1 phosphorylation at Y316 modulates its interaction with SARAF and the activation of SOCE and ICRAC

“…The role of tyrosine phosphorylation in STIM1 function has been scarcely investigated. Tyrosine kinase activation by intracellular Ca 2+ store depletion, and subsequent activation of Ca 2+ entry, has previously been reported (Mills et al, 2015;Sage et al, 1992;Zuo et al, 2011). Interestingly, Ca 2+ store depletion by thapsigargin (TG) has been reported to evoke protein tyrosine phosphorylation in cells loaded with the Ca 2+ chelator BAPTA (Sargeant et al, 1994), indicating that Ca 2+ store depletion itself, and not the subsequent rise in the cytosolic free Ca 2+ concentration ([Ca 2+ ] c ), is sufficient for tyrosine kinase activation.…”

Relaxing Effect of TSU-68, an Antiangiogenic Agent, on Mouse Airway Smooth Muscle

“…3 and 7). Tyrosine kinase-induced smooth muscle contraction is a complicated process that involves plasma membrane depolarization [61] and the phosphorylation of a series of ACh-related receptors [66, 67]. In our study, TSU-68, as a tyrosine kinase inhibitor, may have indirectly polarized the plasma membrane to block VDCCs or may have directly dephosphorylated the ACh-related protein kinase K (PKC) pathway to block NSCCs.…”