Gq-coupled receptors as mechanosensors mediating myogenic vasoconstriction.
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 G(q/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 beta-arrestin. Agonist-independent receptor activation by mechanical stimuli is blocked by specific antagonists and inverse agonists. Increasing the AT(1) 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 AT(1) 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 G(q/11)-coupled receptors function as sensors of membrane stretch in VSM cells.
Mederos y Schnitzler
Michael
M
Institut für Pharmakologie und Toxikologie, Philipps-Universität Marburg, Marburg, Germany.
Storch
Ursula
U
Meibers
Simone
S
Nurwakagari
Pascal
P
Breit
Andreas
A
Essin
Kirill
K
Gollasch
Maik
M
Gudermann
Thomas
T
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D019390:Arrestins / Q000378:metabolism; D002460:Cell Line; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D006801:Humans; D008465:Mechanoreceptors / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D050051:Transient Receptor Potential Channels / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism; D014661:Vasoconstriction; D000071557:beta-Arrestins
D019390:Arrestins; D011945:Receptors, Angiotensin; D043562:Receptors, G-Protein-Coupled; D050051:Transient Receptor Potential Channels; D000071557:beta-Arrestins; D000804:Angiotensin II; D010738:Type C Phospholipases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11