The small GTPase Rac1 is required for smooth muscle contraction. (20th January 2014)

• Record Type: Journal Article
• Authors: Rahman, Awahan; Davis, Benjamin; Lövdahl, Cecilia; Hanumaiah, Veena T.; Feil, Robert; Brakebusch, Cord; Arner, Anders
• Is Part Of: Journal of physiology. Volume 592:Number 5(2014:Mar.)
• Page Start: 915
• Page End: 926
• Publication Date: 2014-01-20
• Subjects: Physiology -- Periodicals; 612.005
• DOI: 10.1113/jphysiol.2013.262998
• Languages: English
• ISSNs: 0022-3751

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="tjp6002-sec-0010" sec-type="section"> <title>Key points</title> <p> <list id="tjp6002-list-0001" list-type="bullet"> <list-item> <p>The role of the small G‐protein Rac1 was investigated in smooth muscle, using a smooth muscle‐specific knockout mouse and pharmacological blockers.</p> </list-item> <list-item> <p>Inhibition of the interaction between Rac1 and upstream regulators inhibited the α‐receptor contractions and potentiated prostaglandin F2α contractions in vascular tissue.</p> </list-item> <list-item> <p>The inhibition was mediated via an attenuation of the Ca<sup>2+</sup> transient.</p> </list-item> <list-item> <p>A global inhibition of Rac1 activity inhibited contractions in response to several agonists in a range of smooth muscle tissues.</p> </list-item> <list-item> <p>The results demonstrate a novel Rac1‐associated signalling pathway for regulation of smooth muscle contraction.</p> </list-item> </list> </p> </sec> <sec id="tjp6002-sec-0020" sec-type="section"> <title>Abstract</title> <p>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<sup>+</sup>, 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 Ca<sup>2+</sup> 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 α<sub>1</sub> receptor responses (phenylephrine) in vascular tissues and potentiated prostaglandin F2α and thromboxane (U46619) receptor responses. The latter potentiating effect occurred at lowered intracellular [Ca<sup>2+</sup>]. These results show that Rac1 activity is required for active contraction in smooth muscle, probably via enabling an adequate Ca<sup>2+</sup> transient. At the same time, specific agonists recruit Rac1 signalling via upstream modulators, resulting in either a potentiation of contraction via Ca<sup>2+</sup> mobilization (α<sub>1</sub> receptor stimulation) or an attenuated contraction via inhibition of Ca<sup>2+</sup> sensitization (prostaglandin and thromboxane receptors).</p> </sec> </abstract>