Rho-kinase, a common final path of various contractile bladder and ureter stimuli

Normal urinary bladder function is based on the proper contraction and relaxation of smooth muscle (SM), which constitutes the majority of the bladder wall. The contraction and relaxation of all SM involves a phosphorylation-dephosphorylation pathway involving the enzymes smooth muscle myosin light chain kinase (SMMLCK) and smooth muscle myosin light chain phosphatase (SMMLCP), respectively. Although originally thought to function just as a passive opposition to SMMLCK-driven SM contraction, it is now clear that SMMLCP activity is under an extremely complex molecular regulation via which SMMLCP inhibition can induce "calcium sensitization." This review provides a thorough summary of the literature regarding the molecular regulation of the SMMLCP with a focus on one of its major inhibitory pathways that is RhoA/Rho-kinase (ROK) including its activation pathways, effector molecules, and its roles in various pathological conditions associated with bladder dysfunction. Newly emerging roles of ROK outside of SM contractility are also discussed. It is concluded that the RhoA/ROK pathway is critical for the maintenance of basal SM tone of the urinary bladder and serves as a common final pathway of various contractile stimuli in rabbits, rats, mice, and pigs as well as humans. In addition, this pathway is upregulated in response to a number of pathological conditions associated with bladder SM dysfunction. Similarly, RhoA/Rho-kinase signaling is essential for normal ureteral function and development and is upregulated in response to ureteral outlet obstruction. In addition to its critical role in bladder SM function, a role of ROK in the urothelium is also beginning to emerge as well as roles for ROK in bladder infection and invasion and metastasis of bladder cancer.