Abstract
Cells respond to diverse types of mechanical stimuli using a wide range of plasma membrane-associated mechanosensitive receptors to convert extracellular mechanical cues into intracellular signaling. G protein-coupled receptors (GPCRs) represent the largest cell surface protein superfamily that function as versatile sensors for a broad spectrum of bio/chemical messages. In recent years, accumulating evidence has shown that GPCRs can also engage in mechano-transduction. According to the GRAFS classification system of GPCRs, adhesion GPCRs (aGPCRs) constitute the second largest GPCR subfamily with a unique modular protein architecture and post-translational modification that are well adapted for mechanosensory functions. Here, we present a critical review of current evidence on mechanosensitive aGPCRs.
Highlights
Due to the unique GPCR proteolysis site (GPS) autoproteolysis and the unusual N-terminal fragment (NTF)-C-terminal fragment (CTF) organization as well as the fact that most adhesion GPCRs (aGPCRs) ligands identified to date are cell surface and/or extracellular matrix (ECM) proteins, it is highly suggestive that some aGPCRs are prone to respond to mechanical disturbance during cell-cell or cell-ECM interaction (Figure 2)
The unusual NTF-CTF bipartite design coupled with the dual cell-adhesive and signaling functions have made aGPCRs credible biosensors for mechano-transduction
The cell-type specific expression characteristics of some aGPCRs such as EMR2, CD97, and GPR56 in circulating leukocytes, VLGR1 in auditory hair cells, and LPHN1 in mechanosensory neurons further highlighted the role of aGPCRs in mechano-sensing
Summary
The functional significance of aGPCRs has been amply documented in various physiological and pathological processes such as brain cortex development [17], immune regulation [18,19,20], fertility [21], and tumorigenesis [22,23] While it is beyond the scope of the present review to discuss the functional roles of aGPCRs (please see [24,25] for detail), the underlying mechanisms for the diverse functions of aGPCRs are mainly due to their complex structural organization and diverse receptor activities that integrate extracellular adhesion and intracellular signaling [26]. Inwe summaarticle, first discuss the structural characteristics aGPCRs rize thewe current understandings of specific aGPCRsand thatactivation function mechanisms as potential of mechanoto explain why they are suited for mechanosensing.
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