Rho kinase

Ishizaki et al. 1996

Rho kinase, also known as ROCK, is an enzyme of the serine/threonine kinase family. Rho kinase is an effector of the small G protein Rho. ROCKs are involved in the regulation of various cellular functions, such as smooth muscle cell contraction, actin cytoskeleton organization, cell adhesion, cell migration, cytokinesis, cell proliferation, and inflammatory cell migration.

Rho kinase consists of two isoforms:

• Rho kinase 1 (ROCK1)

and

• Rho kinase 2 (ROCK2)

The RhoA-Rho kinase cascade is an important signaling pathway for the control of blood vessels, especially renal resistance vessels and renal blood flow. This signaling pathway is involved in numerous cellular control processes.

ROCK is a serine/threonine kinase and is ubiquitously expressed in two isoforms, ROCK I and ROCK II, in many cell types of different species. It is also found primarily in vascular smooth muscle cells, where it is localized predominantly in the cytosol but also in the cell membrane.

Both ROCK isoforms are highly conserved and contain an N-terminal kinase domain followed by a coiled-coil domain and a C-terminal regulator domain. Activation of Rho kinase occurs through the binding of an activated Rho GTPase, particularly RhoA, to the Rho-binding domain of the kinase. This exposes and activates the kinase domain of Rho kinase, leading to phosphorylation of various target proteins. Active ROCK has numerous substrates and is involved in fundamental cell biological processes such as motility, cell growth, and cell differentiation. Disruption of this system can lead to tumor formation and malformations during embryonic development.

In vascular smooth muscle, ROCK specifically regulates cytoskeletal organization and agonist-induced vasoconstriction. The latter occurs by increasing the Ca2+ sensitivity of the muscle cell. Smooth muscle tone is determined by the phosphorylation level of the myosin light chain (MLC). During Ca2+-dependent muscle contraction, the Ca2+-calmodulin complex increases myosin light chain kinase (MLCK) activity, and the MLC is increased in phosphorylation, thus enhancing muscle contraction [30, 38]. Now, when ROCK is activated by an agonist such as AngII via the described signaling pathway, it inhibits the

Myosin light chain phosphatase (MLCP) by phosphorylating myosin phosphatase target subunit 1 (MYPT). The function of MLCP is to dephosphorylate MLC and thus attenuate contraction. Its inhibition further enhances contraction, thereby increasing Ca2+ sensitivity. Furthermore, ROCK promotes Ca2+ influx into the cell [40] and Ca2+ in turn has an activating effect on ROCK. In addition, the RhoA-ROCK signaling pathway has also been shown to be significant for cell differentiation of vascular smooth muscle cells (Reimer N 2017).

There are various substances that can inhibit the activity of Rho kinases. One of these is Y-27632, a selective inhibitor of Rho kinase. Y-27632 binds to the ATP-binding site of Rho kinase, preventing phosphorylation of substrates. Other Rho kinase inhibitors include fasudil, ripasudil, or netarsudil, which also block the ATP-binding site and reduce Rho kinase activity. Inhibition of Rho kinase has therapeutic potential in several medical fields. In cardiovascular medicine, Rho kinase is being investigated as a target for the treatment of hypertension, angina, and pulmonary hypertension. In addition, Rho kinase inhibitors are used in ophthalmology to treat glaucoma by lowering intraocular pressure.

1. Reimer N (2017) The importance of RhoA-Rho kinase and NADPH oxidase for tone regulation of renal resistance arteries of hypertensive Cyp1a1ren-2- transgenic rats. Inaugural dissertation for the degree of Doctor of Medicine of the University Medicine of the Ernst-Moritz-Arndt-University Greifswald.
2. Sun GP et. al.(2006) Involvements of Rho-kinase and TGF-beta Pathways in Aldosterone-Induced Renal Injury J Am Soc Nephrol 17: 2193-2201.