GPCRs Under Flow and Pressure

Abstract

G protein-coupled receptors (GPCRs) are commonly known as membrane-bound cellular sensors for chemical stimuli like small molecules and hormones that activate intracellular signal transduction pathways resulting in cellular responses. However, GPCRs are not only sensitive to agonist stimulation but also to mechanical forces. There is growing evidence that mechanosensitive GPCRs are involved in several physiological and pathophysiological states, such as vascular regulation, cardiac hypertrophy, and preeclampsia. In blood vessels, two different mechanical forces occur that contribute to autoregulation of the vessel tone: shear stress induced by blood flow and wall stretch induced by blood pressure. Recent findings suggest that blood flow activates mechanosensitive GPCRs in endothelial cells resulting in flow-induced vasodilation, and blood pressure activates mechanosensitive GPCRs in vascular smooth muscle cells mediating myogenic vasoconstriction. Seven GPCRs are currently discussed as potential mechanosensors in blood vessels. However, a principal molecular mechanism underlying mechanically induced GPCR activation remained largely elusive. Recent findings suggest that at the molecular level, GPCRs undergo stimulus-specific patterns of conformational changes. Moreover, GPCRs that possess a C-terminal helix 8 (H8), a common feature of many GPCRs, are mechanosensitive, while GPCRs that lack H8 are not mechanosensitive. In addition, transfer of H8 to non-mechanosensitive GPCRs confers whereas elimination of the H8 precludes mechanosensitivity. Thus, there is evidence pinpointing H8 as an essential structural motif that endows GPCRs with mechanosensitivity. Deeper insights into the mechanistic basis of mechanosensation of GPCRs may lay the foundation for a better understanding of the roles of mechanosensitive GPCRs in health and disease.