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Molecular determinants of the mechanosensitivity of G protein‐coupled receptors
Author(s) -
Mederos y Schnitzler Michael,
Storch Ursula,
Erdogmus Serap,
Danner Laura,
Becker Jasmin,
Winter Michaela,
Ziegler Nicole,
Wirth Angela,
Offermanns Stefan,
Hoffmann Carsten,
Gudermann Thomas
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.05324
Subject(s) - mechanosensitive channels , g protein coupled receptor , receptor , chemistry , microbiology and biotechnology , mechanotransduction , signal transduction , stimulus (psychology) , biophysics , ion channel , biology , biochemistry , psychology , psychotherapist
G‐protein coupled receptors (GPCRs) are broadly tuned cellular sensors for chemical stimuli, and also serve as mechanosensors e.g. in vascular regulation and cardiac hypertrophy. The molecular mechanism underlying mechanically induced GPCR activation is still only partially understood. Here we show that mechanosensitive histamine H 1 receptors (H 1 Rs) are endothelial sensors of fluid shear stress and contribute to flow‐induced vasodilation. At the molecular level, H 1 Rs undergo stimulus‐specific patterns of conformational changes supporting the notion that mechanical forces and agonists induce distinct active receptor conformations. GPCRs devoid of C‐terminal helix 8 (H8) lack mechanosensitivity. Conversely, transfer of H8 to non‐responsive GPCRs renders them sensitive to mechanical cues. Disrupting H8 structural integrity by amino acid exchanges impairs mechanosensitivity. Thus, 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 health and disease.