Model Organisms in G Protein–Coupled Receptor Research

Abstract

The study of G protein-coupled receptors (GPCRs) has benefited greatly from experimental approaches that interrogate their functions in controlled, artificial environments. Working in vitro, GPCR receptorologists discovered the basic biologic mechanisms by which GPCRs operate, including their eponymous capacity to couple to G proteins; their molecular makeup, including the famed serpentine transmembrane unit; and ultimately, their three-dimensional structure. Although the insights gained from working outside the native environments of GPCRs have allowed for the collection of low-noise data, such approaches cannot directly address a receptor's native (in vivo) functions. An in vivo approach can complement the rigor of in vitro approaches: as studied in model organisms, it imposes physiologic constraints on receptor action and thus allows investigators to deduce the most salient features of receptor function. Here, we briefly discuss specific examples in which model organisms have successfully contributed to the elucidation of signals controlled through GPCRs and other surface receptor systems. We list recent examples that have served either in the initial discovery of GPCR signaling concepts or in their fuller definition. Furthermore, we selectively highlight experimental advantages, shortcomings, and tools of each model organism.

Adhesion G Protein–Coupled Receptors: From In Vitro Pharmacology to In Vivo Mechanisms

“…In line with this model, overexpression of wildtype but not nonpolymerizing lama2 (the gene encoding the achain of Laminin-211) could suppress myelin defects in gpr126 hypomorphic mutants. This, coupled with the dynamic culture assays described above, supports the notion that Laminin-211 polymerization could be one mechanism that facilitates GPR126-NTF removal in vivo (see also Langenhan et al, 2015).…”

“…Removal of Latrophilin/CIRL results in a dramatic drop of this input-output relationship leading to profound insensitivity toward mechanical stimulation and blurred signal-to-noise discrimination. Genetic experiments have further indicated that Latrophilin/CIRL may act by modulating ionotropic mechanosensors of the transient receptor potential channel family and may impinge on their properties in a mechanostimulus-dependent manner (see also Langenhan et al, 2015). Whether this effect of Latrophilin/CIRL is dependent on NTF, CTF, or both aGPCR fragments acting together remains to be determined.…”

New paradigms in GPCR drug discovery

“…Characterization of these parameters for new compounds promises to be a means of discovering more efficacious GPCR drugs with fewer side effects. 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].…”

“…Genetic variants of the unsaturated fatty acid receptor GPR120 have differential effects on obesity, both in humans (e.g. obesity-associated p.Arg270His mutation) and dogs, which can have implications for therapeutics and nutrition [48]. The encoding of µOR variants by the gene Oprm1 is subject to extensive alternative splicing, including C-terminal truncations.…”

Exploring the Biology of G Protein–Coupled Receptors from In Vitro to In Vivo

“…interpretation of GPCR crystal structures, importance of ligand residence time, GPCR multimers, the promise of biased signaling in vivo, spatial and temporal aspects of GPCR signaling, studying GPCR signaling with resonance energy transfer biosensors in vivo, model organisms in GPCR research, and a novel class of adhesion GPCRs and GPCR signaling networks from a systems biology perspective Langenhan et al, 2015;Lohse and Hofmann, 2015;Luttrell et al, 2015;Monk et al, 2015;Piscitelli et al, 2015;Roth et al, 2015;van Unen et al, 2015;Vischer et al, 2015). Scientists with expertise in in vitro and in vivo GPCR studies participated in the different reviews, thus bridging these fields.…”