Endomembrane-Based Signaling by GPCRs and G-Proteins

Abstract

G-protein-coupled receptors (GPCRs) and G-proteins have a range of roles in many physiological and pathological processes and are among the most studied signaling proteins. A plethora of extracellular stimuli can activate the GPCR and can elicit distinct intracellular responses through the activation of specific transduction pathways. For many years, biologists thought that GPCR signaling occurred entirely on the plasma membrane. However, in recent decades, many lines of evidence have proved that the GPCRs and G-proteins may reside on endomembranes and can start or propagate signaling pathways through the organelles that form the secretory route. How these alternative intracellular signaling pathways of the GPCR and G-proteins influence the physiological and pathological function of the endomembranes is still under investigation. Here, we review the general role and classification of GPCRs and G-proteins with a focus on their signaling pathways in the membrane transport apparatus.

The Adhesion G-Protein-Coupled Receptor GPR115/ADGRF4 Regulates Epidermal Differentiation and Associates with Cytoskeletal KRT1

“…The most unexpected finding of our study is the close colocalization of endogenous GPR115 and KRT1/10, which is strongly supported by immunogold electron microscopy. At first glance, such a colocalization appears unusual for a GPCR that is commonly present at and signaling from extra-and intracellular membranes [31,32]. Is it conceivable that only a GPR115 fragment such as the ECD or a part thereof associates alongside KRT1/10 filaments?…”

Activation of OR10A3 by Suberic Acid Promotes Collagen Synthesis in UVB-Irradiated Dermal Fibroblasts via the cAMP-Akt Pathway

“…G-protein-coupled receptors have long been of interest as molecular targets because they regulate diverse physiological processes and have surface-accessible binding sites; more than 30 percent of US Food and Drug Administration-approved drugs target GPCRs [ 24 , 25 , 26 , 27 ]. Notably, ORs account for nearly half of the GPCRs in humans; however, these ORs were largely excluded as potential molecular targets for human therapy because they were believed to be solely associated with smell-related functions.…”

Comprehensive Spatial Profile of the Orphan G Protein Coupled Receptor GPRC5B Expression in Mouse Brain

“…Similarly, intracellular signaling cascades activated by this orphan receptor are starting to be explored. Indeed, emerging studies on GPRC5A, a close GPRC5 family member, recently depicted a potential role in endomembrane signaling that may be a common feature of this class of orphan GPCRs ( Di Martino et al, 2020 ; Liccardo et al, 2022 ). Therefore, it is possible that GPRC5B may serve different roles according to its specific subcellular location.…”