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

Abstract

Smooth muscle contraction involves regulating myosin light chain phosphorylation and dephosphorylation by myosin light chain kinase and myosin light chain phosphatase. CPI-17 and MYPT1 are crucial for regulating gastrointestinal smooth muscle contraction by inhibiting myosin light chain phosphatase. Integrin signalling involves the dynamic recruitment of several proteins, including FAK, to focal adhesions. FAK tyrosine kinase activation is involved in cell adhesion to the extracellular matrix via integrin signalling. FAK participates in linking the force generated by myofilament activation to the extracellular matrix and throughout the smooth muscle tissue. Here, we show that cholinergic stimulation activates FAK in gastric fundus smooth muscles. Electrical field stimulation in the presence of L-NAME and MRS2500 contracted gastric fundus smooth muscle strips and increased FAK Y397 phosphorylation (pY397). Atropine blocked the contractions and prevented the increase in pY397. The FAK inhibitor PF-431396 inhibited the contractions and the increase in pY397. PF-431396 also inhibited the EFS-induced increase in CPI-17 T38 phosphorylation, and reduced MYPT1 T696 and T853, and myosin light chain S19 phosphorylation. Ca²⁺ influx was unaffected by PF-431396. Nicardipine inhibited the contractions but had no effect on the increase in pY397. PDBu or calyculin A contracted gastric fundus smooth muscle strips Ca²⁺ independently and increased pY397. Our findings suggest that FAK is activated by mechanical forces during contraction, and reveal a novel role of FAK in the regulation of CPI-17 phosphorylation.

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