Adhesion GPCRs as a Putative Class of Metabotropic Mechanosensors

Abstract

Adhesion GPCRs as mechanosensors. Different aGPCR homologs and their cognate ligands have been described in settings, which suggest that they function in a mechanosensory capacity. For details, see text G protein-coupled receptors (GPCRs) constitute the most versatile superfamily of biosensors. This group of receptors is formed by hundreds of GPCRs, each of which is tuned to the perception of a specific set of stimuli a cell may encounter emanating from the outside world or from internal sources. Most GPCRs are receptive for chemical compounds such as peptides, proteins, lipids, nucleotides, sugars, and other organic compounds, and this capacity is utilized in several sensory organs to initiate visual, olfactory, gustatory, or endocrine signals. In contrast, GPCRs have only anecdotally been implicated in the perception of mechanical stimuli. Recent studies, however, show that the family of adhesion GPCRs (aGPCRs), which represents a large panel of over 30 homologs within the GPCR superfamily, displays molecular design and expression patterns that are compatible with receptivity toward mechanical cues (Fig. 1). Here, we review physiological and molecular principles of established mechanosensors, discuss their relevance for current research of the mechanosensory function of aGPCRs, and survey the current state of knowledge on aGPCRs as mechanosensing molecules.

The G protein‐coupled oestrogen receptor, GPER1, mediates direct anti‐inflammatory effects of oestrogens in human cholinergic neurones from the nucleus basalis of Meynert

“…Although further investigations are needed, based on our novel finding concerning a high level of GPER1/vinculin co‐localisation, it is conceivable to hypothesise new possible mechanisms of action of GPER1 in neurones, which could be implicated in the perception of mechanical stimuli to regulate cell adhesivity, migration and synaptic plasticity, with all of these mechanisms being important for neuronal development and function. In this regard, recent studies have identified a family of adhesion GPCRs, comprising a large panel of 30 homologues within the GPCR superfamily displaying receptivity toward mechanical cues . Interestingly, vinculin is involved with anchoring actin to the membrane and plays a role in neurite extension and cell motility .…”

“…Depending on the cellular model, GPER1 was reported not only at the level of the plasma membrane, as expected for a GPCR, but also in the endoplasmic reticulum, Golgi apparatus and perinuclear space, toward mechanical cues. 61 Interestingly, vinculin is involved with anchoring actin to the membrane and plays a role in neurite extension and cell motility. 62,63 Hence, the results obtained in the present study further suggest that GPER1 may mediate the effects of E 2 on neurite outgrowth in hfNBMs, as reported previously.…”

Coincidence Detection of Membrane Stretch and Extracellular pH by the Proton-Sensing Receptor OGR1 (GPR68)

“…7.7 to 6. Cells were first exposed to forskolin and then pH o was dropped (1), forskolin was added simultaneously with the pH o drop (2), or pH o was first dropped and then forskolin added (3).…”

“…The physical environment and its impact on cells are increasingly studied as key determinants of cell, tissue, and organ behavior and fate. Mechanical forces are experienced by all cells; they critically shape physiological processes and can be sensed by a range of proteins [1][2][3]. Different properties of mechanical force (type of force, orientation, and temporal profile) can involve distinct receptors and/or signaling cascades [4].…”

Adhesion GPCRs in Tumorigenesis

“…Many aGPCRs are cleaved at the GPS in the juxtamembrane region which is part of and regulated by a GPCR autoproteolysis-inducing (GAIN) domain and results in an N- (NTF) and a C-terminal fragment (CTF), which remain associated at the cell surface (discussed in depth in [3, 5]). The various possible signaling scenarios resulting from this bipartite structure have been reviewed recently [6, 7] and in [8–10]. …”