PLEIOTROPIC REGULATION OF VASCULAR SMOOTH-MUSCLE TONE BY CYCLIC GMP-DEPENDENT PROTEIN-KINASE

Cyclic GMP (cGMP) mediates vascular smooth muscle relaxation in respon se to nitric oxide and atrial natriuretic peptides. One mechanism by w hich cGMP decreases vascular tone is by lowering cytosolic Ca2+ levels in smooth muscle cells. Although mechanisms by which cGMP regulates c ytosolic Ca2+ are unclear, an important role for the cGMP-dependent pr otein kinase in regulating Ca2+ has been proposed. Cyclic GMP-dependen t protein kinase has been shown to regulate several pathways that cont rol cytosolic Ca2+ levels: inositol 1,4,5-trisphosphate production and action, Ca2+-ATPase activation, and activation of Ca2+-activated K+ c hannels. The pleiotropic action of cGMP-dependent protein kinase is pr oposed to occur through the phosphorylation of important proteins that control several signaling pathways in smooth muscle cells. One potent ial target for cGMP-dependent protein kinase is the class of okadaic a cid-sensitive protein phosphatases that appears to regulate K+ channel s among other potentially important events to reduce cytosolic Ca2+ an d tone. In addition, cytoskeletal proteins are targets for cGMP-depend ent protein phosphorylation, and it is now appreciated that the cytosk eleton may play a key role in signal transduction.