Translating the force—mechano-sensing GPCRs

Abstract

Incorporating mechanical cues into cellular responses allows us to experience our direct environment. Specialized cells can perceive and discriminate between different physical properties such as level of vibration, temperature, or pressure. Mechanical forces are abundant signals that also shape general cellular responses such as cytoskeletal rearrangement, differentiation, or migration and contribute to tissue development and function. The molecular structures that perceive and transduce mechanical forces are specialized cytoskeletal proteins, cell junction molecules, and membrane proteins such as ion channels and metabotropic receptors. G protein-coupled receptors (GPCRs) have attracted attention as metabotropic force receptors as they are among the most important drug targets. This review summarizes the function of mechano-sensitive GPCRs, specifically, the angiotensin II type 1 receptor and adrenergic, apelin, histamine, parathyroid hormone 1, and orphan receptors, focusing particularly on the advanced knowledge gained from adhesion-type GPCRs. We distinguish between shear stress and cell swelling/stretch as the two major types of mechano-activation of these receptors and contemplate the potential contribution of the force-from-lipid and force-from-tether models that have previously been suggested for ion channels.

Mechanosensitive membrane proteins: Usual and unusual suspects in mediating mechanotransduction

“…Ion channels required for hearing are not the only membrane mechanosensors likely to depend on protein filaments for their in situ activation. Other candidates that may depend on extracellular filaments include the MEC-4-dependent channels responsible for touch in C. elegans (Das et al, 2022 Preprint;Emtage et al, 2004;Sanzeni et al, 2019;Katta et al, 2019) and adhesion GPCRs proposed to activate in response to mechanical forces applied to their extracellular domains (Lin et al, 2022a;Wilde et al, 2022). It has also become apparent that channels activated by FFL mechanisms could be modulated by FFF and vice versa.…”

A multi-dimensional view of context-dependent G protein-coupled receptor function

“…Another intriguing example of receptor activation in response to environmental change comes from GPCRs capable of acting as mechanosensors. This includes receptors that can be activated by shear stress in the absence of their endogenous ligands like class A angiotensin II type 1 and sphingosine-1-phosphate receptors, as well as adhesion receptors such as ADGRE5 and ADGRG1 [ 42 ]. Recent work focused on the role of the histamine H1 receptor (H1R) as an endothelial mechanosensor has delved into which structural receptor features allow mechanosensitivity [ 43 ].…”

Role of Adhesion G Protein-Coupled Receptors in Immune Dysfunction and Disorder

“…Thus, GPS proteolysis and the dissociation/dislocation of NTF from CTF are thought as a prerequisite for the tethered agonistic activation of most aGPCRs [ 9 ]. This unusual activation mechanism has recently marked several aGPCRs as functional mechanosensing receptors in many biological systems [ 10 , 11 ]. Apart from this, GPS cleavage-independent and NTF-CTF dissociation-independent activation mechanisms have also been identified, indicating versatile activation modes for aGPCRs.…”