Gq-coupled receptors as mechanosensors mediating myogenic vasoconstriction

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 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 b-arrestin. Agonistindependent 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.

G protein-coupled odorant receptors underlie mechanosensitivity in mammalian olfactory sensory neurons

“…4A). Second, we used another mouse line in which the coding sequence of M71 is replaced with that of β2 adrenergic receptor (β2AR) (24,25), a nonmechanosensitive GPCR (26,27). In contrast to M71 neurons (n = 7 tested at 20 psi), β2AR→M71 neurons (n = 7; P < 0.001, Fisher's exact test) failed to respond to puffs of Ringer's solution or acetophenone (a ligand for M71), but did respond to the β2AR agonist isoproterenol (Fig.…”

Flow enhances the agonist-induced responses of the bradykinin receptor (B2) because of its lectinic nature: Role of its oligosaccharide environment

“…Our hypothesis is that the flow response requires that the sensor, composed of a lectinic transducing protein in a specific oligosaccharide environment, detects flow/mechanical stress through lectin-oligosaccharide interactions [1,2,8,12,14,26,51]. This concept would apply to other flow-sensitive luminal endothelial membrane protein structures listed in Table 3.…”

“…Lastly, it is inaccurate to assume that hormone and electrical stimuli act on transmembrane effector proteins in a cell membrane (a lipid bilayer) which is denuded of extracellular specific anchor structures i. e. a "baldheaded" membrane [1,2,46]. These pervasive models are a conceptual oversimplification since electron microscopic, biochemical, and now functional studies show that many of these transmembrane proteins are lectins and are surrounded and bound to a dense mesh of specific oligosaccharides complexes.…”

“…The molecular and physical mechanisms by which endothelial cells transduce flow into biochemical responses are ambiguous [1][2][3][4][5], because the transducing molecules directly affected by flow, the "mechanosensors", are unknown. Flow sensing properties likely reside in the luminal endothelial surface; constituted by the cell membrane and glycocalyx which is acted by flow [6][7][8][9][10][11][12][13].…”

Receptors, G proteins, and integration of calcium signalling

“…Vascular smooth muscle cells harbor a certain plasticity, because under certain hemodynamic conditions or after vascular injury, they lose their contractile, differentiated phenotype and become dedifferentiated, synthetic, and more motile. Physiological vascular regulation such as the myogenic response [19,20] as well as the balance between these two extreme ends of a differentiation spectrum is controlled by G protein-coupled receptors. In his recent work, Offermanns and other laboratories provided compelling evidence to show that pro-contractile G protein signals are critical regulators of vascular smooth muscle differentiation as well.…”