Trans‐synaptic regulation of group III mGluR pharmacology by endogenous allosteric modulators implicated in neuropsychiatric disease

Abstract

Functional characterization of the GPCR interactome has focused predominantly on intracellular interacting‐proteins, yet GPCRs are increasingly found in complex with extracellular proteins. Extracellular leucine rich repeat fibronectin type III domain containing 1 (ELFN1) was recently reported to physically anchor mGluR6 and mGluR7 across retinal and hippocampal synapses, respectively; however, the consequence and extent of trans‐synaptic interactions on GPCR physiology and pharmacology had been unknown. We explored the functional implications of ELFN1‐mGluR interactions by developing a novel transcellular GPCR signaling assay platform to monitor changes in mGluR activity in one cell following its exposure to separate ELFN1‐containing cells. Using this platform, we found the first evidence of allosteric modulation of GPCR activity in trans; whereby ELFN1‐expressing cells in co‐culture altered both agonist‐induced and constitutive receptor activity of group III mGluRs expressed in separate cell populations. We further adapted this platform for various readouts and determined transcellular ELFN1‐mediated alterations of group III mGluR cAMP signaling was not a consequence of receptor membrane expression or desensitization, but instead a direct consequence of altered G protein activation as seen by BRET‐based real‐time kinetic assays. Furthermore, we have identified additional trans‐synaptic binding partners of group III mGluRs with previously unknown function and demonstrate selective pharmacological consequence and relevance to neuropsychiatric disease. Our findings demonstrate that accepted principles of group III mGluR pharmacology are critically altered via extracellular interactions with endogenous trans‐synaptic allosteric modulators, and disruption of these interactions may endow susceptibilities to neuropsychiatric disease.Support or Funding InformationThis work was supported by NIH Grants EY018139 and DA026405 (to K.A.M.). H.A.D. is the recipient of a Canadian Institutes of Health Research Postdoctoral Fellowship award.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.