title: The small GTPase Rac1 is required for smooth muscle contraction.
abstract: The role of the small GTP-binding protein Rac1 in smooth muscle contraction was examined using small molecule inhibitors (EHT1864, NSC23766) and a novel smooth muscle-specific, conditional, Rac1 knockout mouse strain. EHT1864, which affects nucleotide binding and inhibits Rac1 activity, concentration-dependently inhibited the contractile responses induced by several different modes of activation (high-K+, phenylephrine, carbachol and protein kinase C activation by phorbol-12,13-dibutyrate) in several different visceral (urinary bladder, ileum) and vascular (mesenteric artery, saphenous artery, aorta) smooth muscle tissues. This contractile inhibition was associated with inhibition of the Ca2+ transient. Knockout of Rac1 (with a 50% loss of Rac1 protein) lowered active stress in the urinary bladder and the saphenous artery consistent with a role of Rac1 in facilitating smooth muscle contraction. NSC23766, which blocks interaction between Rac1 and some guanine nucleotide exchange factors, specifically inhibited the α1 receptor responses (phenylephrine) in vascular tissues and potentiated prostaglandin F2α and thromboxane (U46619) receptor responses. The latter potentiating effect occurred at lowered intracellular [Ca2+]. These results show that Rac1 activity is required for active contraction in smooth muscle, probably via enabling an adequate Ca2+ transient. At the same time, specific agonists recruit Rac1 signalling via upstream modulators, resulting in either a potentiation of contraction via Ca2+ mobilization (α1 receptor stimulation) or an attenuated contraction via inhibition of Ca2+ sensitization (prostaglandin and thromboxane receptors).
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, von Eulers väg 8, SE 171 77 Stockholm, Sweden. Anders.Arner@ki.se.
authors.forename: Awahan
authors.initials: A
authors.lastname: Rahman
authors.forename: Benjamin
authors.initials: B
authors.lastname: Davis
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lövdahl
authors.forename: Veena T
authors.initials: VT
authors.lastname: Hanumaiah
authors.forename: Robert
authors.initials: R
authors.lastname: Feil
authors.forename: Cord
authors.initials: C
authors.lastname: Brakebusch
authors.forename: Anders
authors.initials: A
authors.lastname: Arner
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D005260:Female; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000502:physiology*; D009479:Neuropeptides / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
chemical_list: D009479:Neuropeptides; C484602:Rac1 protein, mouse; D020830:rac1 GTP-Binding Protein