Abstract
Erectile dysfunction (ED) is a highly prevalent and often under-treated condition. Erection is basically a spinal reflex that can be initiated by recruitment of penile afferents but also by visual, olfactory and imaginary stimuli. The generated nervous signals will influence the balance between contractile and relaxant factors, which control the degree of contraction of penile corporal cavernosal smooth muscles and, thus, determine the erectile state of the penis. The different steps involved in neurotransmission, impulse propagation and intracellular transduction of neural signals may be changed in different types of ED. Recent studies have revealed important roles for the small GTPase RhoA and its effector, Rhokinase in regulating cavernosal smooth muscle tone. The RhoA/Rho-kinase pathway modulates the level of phosphorylation of the myosin light chain, mainly through inhibition of myosin phosphatase, and contributes to agonistinduced Ca2+-sensitization in smooth muscle contraction. Changes in this pathway may contribute to ED in various patient subgroups (e.g. hypertension, diabetes, hypogonadism). This review summarizes the importance of Rho-kinase signaling in the erectile response and introduces the evidence pointing to RGS-containing Rho-guanine nucleotide exchange factors (GEFs) as critical mediators of RhoA-GTPase activation in cavernosal smooth muscle and its possible compartmentalization in the caveolae. In addition, we suggest that the design of selective inhibitors of these GEFs might represent a novel class of pharmacological agents to treat ED.
Keywords: Corpus cavernosum, erectile dysfunction, RhoA/Rho-kinase pathway, RhoGEFs, caveolae
Current Pharmaceutical Design
Title: Rho-Kinase and RGS-Containing RhoGEFs as Molecular Targets for the Treatment of Erectile Dysfunction
Volume: 11 Issue: 31
Author(s): A. E. Linder, R. C. Webb, T. M. Mills, Z. Ying, R. W. Lewis and C. E. Teixeira
Affiliation:
Keywords: Corpus cavernosum, erectile dysfunction, RhoA/Rho-kinase pathway, RhoGEFs, caveolae
Abstract: Erectile dysfunction (ED) is a highly prevalent and often under-treated condition. Erection is basically a spinal reflex that can be initiated by recruitment of penile afferents but also by visual, olfactory and imaginary stimuli. The generated nervous signals will influence the balance between contractile and relaxant factors, which control the degree of contraction of penile corporal cavernosal smooth muscles and, thus, determine the erectile state of the penis. The different steps involved in neurotransmission, impulse propagation and intracellular transduction of neural signals may be changed in different types of ED. Recent studies have revealed important roles for the small GTPase RhoA and its effector, Rhokinase in regulating cavernosal smooth muscle tone. The RhoA/Rho-kinase pathway modulates the level of phosphorylation of the myosin light chain, mainly through inhibition of myosin phosphatase, and contributes to agonistinduced Ca2+-sensitization in smooth muscle contraction. Changes in this pathway may contribute to ED in various patient subgroups (e.g. hypertension, diabetes, hypogonadism). This review summarizes the importance of Rho-kinase signaling in the erectile response and introduces the evidence pointing to RGS-containing Rho-guanine nucleotide exchange factors (GEFs) as critical mediators of RhoA-GTPase activation in cavernosal smooth muscle and its possible compartmentalization in the caveolae. In addition, we suggest that the design of selective inhibitors of these GEFs might represent a novel class of pharmacological agents to treat ED.
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Cite this article as:
Linder E. A., Webb C. R., Mills M. T., Ying Z., Lewis W. R. and Teixeira E. C., Rho-Kinase and RGS-Containing RhoGEFs as Molecular Targets for the Treatment of Erectile Dysfunction, Current Pharmaceutical Design 2005; 11 (31) . https://dx.doi.org/10.2174/138161205774913390
DOI https://dx.doi.org/10.2174/138161205774913390 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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