Calcium Sensitization and the RhoA/Rho Kinase Pathway

In addition to calcium-dependent mechanisms of activation, recent studies have dem-onstrated the presence of a calcium-independent pathway that further regulates corporal smooth muscle contraction. Originally described in other smooth muscle types, this pro-cess, termed calcium sensitization, is regulated by the small, monomeric G protein RhoA and its immediate downstream target Rho-kinase (ROK). Following its activation, ROK inhibits MLC phosphatase (or smooth muscle myosin phosphatase) through phospho-rylation of its regulatory subunit (smooth muscle myosin phosphatase-1M), leading to sensitization of myofilaments to Ca2+. Both RhoA and ROK have been demon-strated in the corpora of several animal species as well as human corporal tissue. Furthermore, intracavernosal injection as well as topical application of the ROK inhibi-tor Y-27632 resulted in an increased erectile response, as demonstrated in an in vivo rat model . This pathway apparently acts via a NO-independent pathway, because co-administration of NO synthase (NOS) inhibitors to animals injected with Y-27632 did not alter the erectile response. Chitaley et al. also demonstrated that transfection of rats with a dominant-negative RhoA enhanced erectile function in rats.

Finally, ROK likely potentiates corporal smooth muscle tone via a common pathway involving ET-1 and noradrenaline-induced vasoconstriction. Therefore, agents target-ing the RhoA/ROK pathway are potential targets for the treatment of erectile dysfunction.