Functional Consequences of GPCR Heterodimerization: GPCRs as Allosteric Modulators

Abstract

G Protein Coupled Receptors (GPCRs) represent the largest family of membrane proteins in the human genome, are the targets of approximately 25% of all marketed pharmaceuticals, and the focus of intensive research worldwide given that this superfamily of receptors is as varied in function as it is ubiquitously expressed among all cell types. Increasing evidence has shown that the classical two part model of GPCR signaling (one GPCR, one type of heterotrimeric G protein) is grossly oversimplified as many GPCRs can couple to more than one type of G protein, each subunit of the heterotrimeric G protein can activate different downstream effectors, and, surprisingly, other GPCRs can affect receptor behavior in G protein-independent ways. The concept of GPCR heterodimerization, or the physical association of two different types of GPCRs, presents an unexpected mechanism for GPCR regulation and function, and provides a novel target for pharmaceuticals. Here we present a synopsis of the functional consequences of GPCR heterodimerization in both in vitro and in vivo studies, focusing on the concept of GPCRs as allosteric modulators. Typically, an allosteric modulator is a ligand or molecule that alters a receptor's innate functional properties, but here we propose that in the case of GPCR heterodimers, it is the physical coupling of two receptors that leads to changes in cognate receptor signaling.

Interplay Between Angiotensin II Type 1 Receptor and Thrombin Receptor Revealed by Bioluminescence Resonance Energy Transfer Assay

“…Indeed, in the absence of PAR1 overexpression, while thrombin did not affect the BRET signals, its combination strongly potentiated AngIImediated BRET increase ( Figures 3A, C) indicating a positive allosteric action of thrombin probably through its endogenously expressed receptors (PAR1 and/or PAR4) in HEK293 cells. This is consistent with the well-established link between the concept of allostery and the interactions between GPCRs highlighting the allosteric modulation between various GPCRs (Springael et al, 2007;Haack and McCarty, 2011;Gomes et al, 2016) such as GABAb heterodimer as well as heterodimers involving glutamate receptors (Pin and Bettler, 2016). Moreover, our data revealed that the activation of both receptors, AT1R and PAR1, was more efficient than their single activation with BRET effects that were even more than additive.…”

G Protein–Coupled Receptor Heteromers

“…Furthermore, such models could be used to facilitate in silico identification of small-molecule heteromer-selective antagonists, which could then be tested for their heteromer selectivity and therapeutic potential. Moreover, it is now evident that GPCR heteromerization is tightly linked to other important concepts, including allosterism (131, 132) and biased signaling (90, 133). Therefore, new GPCR-based drug screening programs should consider, as much as possible, the potential contribution of different GPCR heteromers and their signaling pathways.…”

Processing, signaling, and physiological function of chemerin

“…Heteromerization of GPCRs is known to affect signaling pathways, ligand binding affinity, as well as internalization behavior . De Poorter et al have demonstrated CMKLR1 heteromerization with C‐X‐C chemokine receptor type 4 and C‐C chemokine receptor type 7 (CCR7) in stably transfected Chinese hamster ovary (CHO) cells with bioluminescence resonance energy transfer‐assays.…”