Rho-kinase and RGS-containing RhoGEFs as molecular targets for the treatment of erectile dysfunction

A. E. Linder, R Clinton Webb, T. M. Mills, Z. Ying, Ronald W Lewis, C. E. Teixeira

Research output: Contribution to journalReview article

14 Citations (Scopus)

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, Rho-kinase 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 agonist-induced 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.

Original languageEnglish (US)
Pages (from-to)4029-4040
Number of pages12
JournalCurrent Pharmaceutical Design
Volume11
Issue number31
DOIs
StatePublished - Dec 1 2005

Fingerprint

Rho Guanine Nucleotide Exchange Factors
rho-Associated Kinases
Erectile Dysfunction
Smooth Muscle
Myosin-Light-Chain Phosphatase
Guanine Nucleotide Exchange Factors
Caveolae
Myosin Light Chains
Hypogonadism
Monomeric GTP-Binding Proteins
GTP Phosphohydrolases
Penis
Therapeutics
Muscle Contraction
Synaptic Transmission
Reflex
Signal Transduction
Phosphorylation
Pharmacology
Hypertension

Keywords

  • Caveolae
  • Corpus cavernosum
  • Erectile dysfunction
  • RhoA/Rho-kinase pathway
  • RhoGEFs

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

Cite this

Rho-kinase and RGS-containing RhoGEFs as molecular targets for the treatment of erectile dysfunction. / Linder, A. E.; Webb, R Clinton; Mills, T. M.; Ying, Z.; Lewis, Ronald W; Teixeira, C. E.

In: Current Pharmaceutical Design, Vol. 11, No. 31, 01.12.2005, p. 4029-4040.

Research output: Contribution to journalReview article

Linder, A. E. ; Webb, R Clinton ; Mills, T. M. ; Ying, Z. ; Lewis, Ronald W ; Teixeira, C. E. / Rho-kinase and RGS-containing RhoGEFs as molecular targets for the treatment of erectile dysfunction. In: Current Pharmaceutical Design. 2005 ; Vol. 11, No. 31. pp. 4029-4040.
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