Article
- The EMBO Journal (2008) 27, 3092 - 3103
- doi:10.1038/emboj.2008.233
Published online: 6 November 2008
There is a Have you seen ...? (January 2009) associated with this Article.
Subject Category:
Gq-coupled receptors as mechanosensors mediating myogenic vasoconstriction
Michael Mederos y Schnitzler1,a, Ursula Storch1,a, Simone Meibers1, Pascal Nurwakagari1, Andreas Breit1, Kirill Essin2, Maik Gollasch2 and Thomas Gudermann1,3
- Institut für Pharmakologie und Toxikologie, Philipps-Universität Marburg, Marburg, Germany
- Charité Campus Virchow, Medizinische Klinik m.S. Nephrologie und Internistische Intensivmedizin und ECRC Berlin-Buch, Berlin, Germany
- Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität, München, Germany
Correspondence to:
Thomas Gudermann, Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, Goethestrasse 33, D-80336 München, Germany. Tel.: +49 89 2180 75700/2; Fax: +49 89 2180 75701; E-mail: thomas.gudermann@lrz.uni-muenchen.de
aThese authors contributed equally to this work
Received 16 May 2008; Accepted 13 October 2008
Abstract
Despite the central physiological function of the myogenic response, the underlying signalling pathways and the identity of mechanosensors in vascular smooth muscle (VSM) are still elusive. In contrast to present thinking, we show that membrane stretch does not primarily gate mechanosensitive transient receptor potential (TRP) ion channels, but leads to agonist-independent activation of Gq/11-coupled receptors, which subsequently signal to TRPC channels in a G protein- and phospholipase C-dependent manner. Mechanically activated receptors adopt an active conformation, allowing for productive G protein coupling and recruitment of 
-arrestin. Agonist-independent receptor activation by mechanical stimuli is blocked by specific antagonists and inverse agonists. Increasing the AT1 angiotensin II receptor density in mechanically unresponsive rat aortic A7r5 cells resulted in mechanosensitivity. Myogenic tone of cerebral and renal arteries is profoundly diminished by the inverse angiotensin II AT1 receptor agonist losartan independently of angiotensin II (AII) secretion. This inhibitory effect is enhanced in blood vessels of mice deficient in the regulator of G-protein signalling-2. These findings suggest that Gq/11-coupled receptors function as sensors of membrane stretch in VSM cells.
Keywords:
- AT1 receptor,
- mechanotransduction,
- smooth muscle cell,
- transient receptor potential
