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.
Highlights
Given that of the 266 human targets for approved drugs, 27% correspond to family A G Protein Coupled Receptors (GPCRs) [1], it is not surprising that over the last fifteen years extensive efforts have been devoted to refining existing pharmaceuticals, and identifying new drugs that target and modulate GPCRs
Allosteric modulation of GPCRs is a topic of great interest, and has been the subject of a substantial body of literature; due to space limitations, we are unable to reference every paper and, instead, will focus only on seminal studies that are relevant to the concept of modulation of one receptor by another
We propose that a second GPCR can act as an allosteric modulator of a GPCR
Summary
Given that of the 266 human targets for approved drugs, 27% correspond to family A GPCRs [1], it is not surprising that over the last fifteen years extensive efforts have been devoted to refining existing pharmaceuticals, and identifying new drugs that target and modulate GPCRs. Given that of the 266 human targets for approved drugs, 27% correspond to family A GPCRs [1], it is not surprising that over the last fifteen years extensive efforts have been devoted to refining existing pharmaceuticals, and identifying new drugs that target and modulate GPCRs This endeavor was further complicated by the discovery that different GPCRs were capable of physically associating or heterodimerizing, often changing the conventional signaling pathway of a given receptor. Receptor heterodimerization can have substantial consequences on the binding of ligands, as discussed recently by Birdsall [2]. We will provide examples of GPCR heterodimerization and the functional consequences thereof within the framework of allosteric modulation, focusing more heavily on the consequences of heterodimerization on receptor function downstream of ligand binding. We propose that instead of solely investigating the consequences of GPCR-GPCR interaction in terms of changes in signaling or trafficking of a single receptor, one should consider the physical association with a second receptor as a potential modulator of GPCR activity
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