PROTEIN-TYROSINE PHOSPHORYLATION IN SMOOTH-MUSCLE - A POTENTIAL COUPLING MECHANISM BETWEEN RECEPTOR ACTIVATION AND INTRACELLULAR CALCIUM

This review addresses a rapidly growing body of evidence suggesting th at enhanced protein tyrosine phosphorylation may be a previously unrec ognized mechanism for coupling receptor activation of vascular smooth muscle cells to increases in the intracellular concentration of Ca2+ a nd contraction. The hypothesis proposes that activation of diverse typ es of receptors that are not tyrosine kinase promotes stimulation of a cytosolic tyrosine kinase. In turn, the activated kinase induces tyro sine phosphorylation of substrates that are linked to regulatory mecha nisms for release of intracellular Ca2+ stored in the sarcoplasmic ret iculum and to regulatory mechanisms for influx of extracellular Ca2+. Within this framework, we examine some relevant functional aspects of receptor and nonreceptor tyrosine kinases in different types of cells, the emerging relationships between tyrosine kinase activity and regul ation of intracellular Ca2+, We review studies of nonreceptor tyrosine kinase activity in vascular smooth muscle cells suggesting that a phy siologically relevant kinase may be the enzyme called pp60(c-src). Dat a that appear to link tyrosine phosphorylation to contraction of smoot h muscle are examined, particularly with respect to results obtained w ith tyrosine kinase inhibitors and measures of changes in tyrosine pho sphorylation, Next, we review studies with cultured vascular smooth mu scle cells that point to potential coupling between receptor activatio n, enhanced tyrosine phosphorylation of substrates such as the GTPase activating protein for ras, and the gamma-1 isoform of phospholipase C , and mechanisms controlling Ca2+ influx and release. Emphasis is plac ed on examining the strengths and weaknesses of different experimental approaches, Lastly, a summary of the data is provided which calls att ention to some major issues requiring resolution to permit acceptance or rejection of the underlying hypothesis, and we briefly address some of its possible pathophysiological implications.