Helix 8 is the essential structural motif of mechanosensitive GPCRs

Serap Erdogmus, Ursula Storch, Laura Danner, Jasmin Becker, Michaela Winter, Nicole Ziegler, Angela Wirth, Stefan Offermanns, Carsten Hoffmann, Thomas Gudermann () and Michael Mederos y Schnitzler ()
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Serap Erdogmus: Ludwig Maximilian University of Munich
Ursula Storch: Ludwig Maximilian University of Munich
Laura Danner: Ludwig Maximilian University of Munich
Jasmin Becker: Ludwig Maximilian University of Munich
Michaela Winter: Ludwig Maximilian University of Munich
Nicole Ziegler: Julius Maximilian University of Würzburg
Angela Wirth: Department of Pharmacology
Stefan Offermanns: Department of Pharmacology
Carsten Hoffmann: Friedrich Schiller University Jena
Thomas Gudermann: Ludwig Maximilian University of Munich
Michael Mederos y Schnitzler: Ludwig Maximilian University of Munich

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13722-0

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