Involvement of small GTPases in the regulation of smooth muscle contraction.
Neurohumoral stimulation of smooth muscle leads to an increased responsiveness of the myofilaments to Ca2+. This review provides a summary of the data that suggest that the signalling from the membrane-bound serpentine receptors to the contractile apparatus leading to the increase in Ca(2+)-sensitivity requires the activation of the Ras-related low molecular mass GTPase Rho. In smooth muscle permeabilized with alpha-toxin or beta-escin, the increase in force elicited by different agonists at fixed [Ca2+] (Ca(2+)-sensitization) can be inhibited by bacterial toxins (EDIN, and exoenzyme C3) which ADP-ribosylate and inactivate Rho proteins. Moreover, the agonist-induced increase in Ca(2+)-sensitivity can be mimicked by constitutively active recombinant Rho proteins. The physiological relevance of this mechanism is suggested by the fact that toxins that are internalized into intact cells (toxin B from C. difficile and a chimeric toxin (DC3B) consisting of C3 and the (non-catalytic) B fragment of diphteria toxin (inhibit the tonic phase of an agonist-induced contraction. Toxin B inhibits contraction without affecting the intracellular Ca(2+)-transient determined with fura-2. However, it inhibits phosphorylation of the regulatory light chains of myosin (MLC). Rho has been suggested to activate a Rho-associated kinase which in turn phosphorylates the myosin binding subunit of the myosin light chain phosphatase. This would lead to an increase in phosphorylation of MLC and hence of force at constant Ca2+. The Ca(2+)-sensitizing effect of agonists is also inhibited by tyrosine kinase inhibitors. This suggests the possibility that in smooth muscle, like in non-muscle cells, there is a cross-talk between Rho and tyrosine kinases.
Pfitzer
G
G
Institut für Vegetative Physiologie, Universität zu Köln, Germany.
Arner
A
A
D008841:Actin Cytoskeleton / Q000502:physiology; D000818:Animals; D020558:GTP Phosphohydrolases / Q000502:physiology*; D006801:Humans; D009119:Muscle Contraction / Q000502:physiology*; D009130:Muscle, Smooth / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D020558:GTP Phosphohydrolases