G Protein–Coupled Receptor (GPCR) Expression in Native Cells: “Novel” endoGPCRs as Physiologic Regulators and Therapeutic Targets

Abstract

G protein-coupled receptors (GPCRs), the largest family of signaling receptors in the human genome, are also the largest class of targets of approved drugs. Are the optimal GPCRs (in terms of efficacy and safety) currently targeted therapeutically? Especially given the large number (∼120) of orphan GPCRs (which lack known physiologic agonists), it is likely that previously unrecognized GPCRs, especially orphan receptors, regulate cell function and can be therapeutic targets. Knowledge is limited regarding the diversity and identity of GPCRs that are activated by endogenous ligands and that native cells express. Here, we review approaches to define GPCR expression in tissues and cells and results from studies using these approaches. We identify problems with the available data and suggest future ways to identify and validate the physiologic and therapeutic roles of previously unrecognized GPCRs. We propose that a particularly useful approach to identify functionally important GPCRs with therapeutic potential will be to focus on receptors that show selective increases in expression in diseased cells from patients and experimental animals.

GPR68, a proton‐sensing GPCR, mediates interaction of cancer‐associated fibroblasts and cancer cells

“…Our use of TaqMan GPCR arrays and RNA sequencing as unbiased approaches to identify and quantify GPCRs in CAFs revealed that CAFs express many GPCRs. We observed an excellent correlation of GPCR expression data from TaqMan GPCR arrays and RNA sequencing but not with Affymetrix microarray data (not shown), which raises questions regarding the utility of such microarray data with respect to expression of GPCRs, especially because GPCRs tend express less than many other transcripts (47).…”

Interrogating the Spatiotemporal Landscape of Neuromodulatory GPCR Signaling by Real-Time Imaging of cAMP in Intact Neurons and Circuits

“…The majority of these neuromodulatory inputs are processed by G protein Coupled Receptors (GPCRs), that influence many aspects of neuronal physiology through the mobilization of second messenger cascades (Gainetdinov et al, 2004; Wettschureck and Offermanns, 2005). With an excess of 800 members, GPCRs are capable of exerting unique effects on neuronal activity owning to their prominent heterogeneity in expression across neuronal populations and differences in subcellular localization (Insel et al, 2015; Magalhaes et al, 2012; Regard et al, 2008). Despite the tremendous diversity, GPCR signals converge downstream and multiple receptors modulate a limited set of second messengers.…”

New paradigms in GPCR drug discovery

“…Most of the roughly 400 nonolfactory, human GPCRs have not yet been exploited as pharmaceutical targets [141]. There are still ~120 orphan GPCRs for which the endogenous ligand is unknown, but even for hundreds of nonorphan GPCRs there is still untapped potential.…”

“…Also, it is important to recognize that the effects of native GPCRs may not always be extrapolated from in vitro data; the appropriate selection of model in vivo systems and organisms is important [48]. Furthermore, the expression pattern and physiological roles of a given GPCR can be altered in a disease state [141]. Also, the effects of acute versus chronic drug administration can be differ or even be opposite [49].…”