Rho Kinase (ROCK) Inhibitors
Rho kinase (ROCK), a serine/threonine kinase, serves as a target protein for small GTP-binding protein Rho. It serves as an important mediator of numerous cellular functions, including focal adhesions, motility, smooth muscle contraction, and cytokinesis. In smooth muscle, ROCK plays an important role in Ca2+ sensitization and the control of vascular tone. It modulates the level of phosphorylation of the myosin II light chain of myosin II, mainly through inhibition of myosin phosphatase, and contributes to agonist-induced Ca2+ sensitization in smooth muscle contraction.
Rho kinase is found in two forms, ROCK 1 (ROCKΒ; p160-ROCK) and ROCK 2 (ROCKα). Both ROCK 1 and ROCK 2 contain an amino-terminal catalytic kinase domain, a central coiled-coil domain of about 600 amino acids, and a carboxyl-terminal pleckstrin homology (PH) domain that is split by a cysteinerich region. Rho/GTP interacts with the C-terminal portion of the central coiled-coil domain and activates the kinase activity of ROCK. Since the ROCK-mediated pathway plays important roles in vascular smooth muscle contraction, cell adhesion, and cell motility, it has gained importance in the pathogenesis of atherosclerosis. Higher ROCK activity has been associated with endothelial cell dysfunction, cerebral ischemia, coronary vasospasms, and metabolic syndrome. Hence, ROCK inhibitors are gaining importance as therapeutic tools. A long-term inhibition of ROCK is reported to block the development of coronary arteriosclerotic lesions.
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