Abstract
G-protein coupled receptors (GPCRs) are versatile cellular sensors for chemical stimuli, but also serve as mechanosensors involved in various (patho)physiological settings like vascular regulation, cardiac hypertrophy and preeclampsia. However, the molecular mechanisms underlying mechanically induced GPCR activation have remained elusive. Here we show that mechanosensitive histamine H1 receptors (H1Rs) are endothelial sensors of fluid shear stress and contribute to flow-induced vasodilation. At the molecular level, we observe that H1Rs undergo stimulus-specific patterns of conformational changes suggesting that mechanical forces and agonists induce distinct active receptor conformations. GPCRs lacking C-terminal helix 8 (H8) are not mechanosensitive, and transfer of H8 to non-responsive GPCRs confers, while removal of H8 precludes, mechanosensitivity. Moreover, disrupting H8 structural integrity by amino acid exchanges impairs mechanosensitivity. Altogether, H8 is the essential structural motif endowing GPCRs with mechanosensitivity. These findings provide a mechanistic basis for a better understanding of the roles of mechanosensitive GPCRs in (patho)physiology.
Highlights
G-protein coupled receptors (GPCRs) are versatile cellular sensors for chemical stimuli, and serve as mechanosensors involved in variousphysiological settings like vascular regulation, cardiac hypertrophy and preeclampsia
To investigate a potential physiological role for the mechanosensitive H1 receptors (H1Rs) in flowinduced endothelial stimulation, we first investigated its expression levels in primary endothelial cells derived from human umbilical veins (HUVEC) serving as a cell model to analyze the mechanosensitivity of endogenously expressed H1Rs
H1R showed more than 12-fold higher mRNA expression levels than other Gq/11-protein coupled receptors and more than 4-fold higher levels than Gs-protein coupled βadrenergic receptors. mRNA expression levels of other mechanosensitive GPCRs like V1AR, cysteinyl leukotriene 1 receptors (CysLT1R), GPR68, D5 receptors (D5R) and parathyroid hormone 1 receptors (PTH1R) were below the detection limit. mRNA expression of the mechanosensitive AT 1 receptors (AT1R) was more than 400-fold lower than that of H1R suggesting a negligible role of AT1R for mechanosensation in HUVECs
Summary
G-protein coupled receptors (GPCRs) are versatile cellular sensors for chemical stimuli, and serve as mechanosensors involved in various (patho)physiological settings like vascular regulation, cardiac hypertrophy and preeclampsia. GPCRs serve as molecular targets for about 30% of all approved drugs[1] They are versatile cellular sensors activated by hormones and neurotransmitters, and by physical and chemical stimuli such as voltage[2,3,4,5,6], ions[7], and mechanical forces[8,9]. PIEZO1 has been identified as an endothelial sensor of shear stress that evokes ATP and adrenomedullin release causing GPCR and eNOS activation and resultant nitrogen oxide (NO) production thereby leading to vasodilation[37,38]
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