PROTEIN-TYROSINE PHOSPHORYLATION, CELLULAR CA2-MUSCLE(, AND CA2+ SENSITIVITY FOR CONTRACTION OF SMOOTH)

Our studies are guided by the novel hypothesis that protein tyrosine p hosphorylation is an important mechanism for regulating contraction of smooth muscle. Several lines of evidence are reviewed which suggest t hat enhanced tyrosine phosphorylation participates in mechanisms that regulate cytosolic Ca2+ and Ca2+ sensitivity for contraction. First, v anadate-induced contraction of guinea-pig taenia coli is functionally linked to enhanced protein tyrosine phosphorylation of at least three substrates, apparently resulting from vanadate-mediated inhibition of protein tyrosine phosphatase activity. Second, vanadate-induced contra ction is dependent on extracellular Ca2+. Third, increases in cytosoli c Ca2+ resulting from stimulation of alpha(1)-adrenergic receptors in cultured canine vascular smooth muscle cells are associated with enhan ced tyrosine phosphorylation and are inhibited by genistein, a potent inhibitor of tyrosine kinase activity. Fourth, genistein markedly and reversibly suppresses Ca2+ sensitivity for contraction in ileal longit udinal smooth muscle permeabilized with staphylococcal a-toxin. Moreov er, the same or similar substrates (e.g., 42-45, 70, 80-85, 95, 100, 1 10, 116, and 205 kDa) are tyrosine phosphory lated in response to Ca2 or stimulation of muscarinic or alpha(1)-adrenergic receptors. Collec tively, these data strongly suggest that tyrosine phosphorylation is a n important mechanism for regulation of smooth muscle contraction.