Probing the unusual functional interaction between mGluR1 and mGluR5.

Abstract

Metabotropic glutamate receptors (mGluRs) are class C G protein coupled receptors with widespread expression in the central nervous system. Unlike many GPCRs, mGluRs exist and function as obligate, disulfide linked dimers. While all mGluRs can form homodimers, and many can heterodimerize, we have recently published a paper demonstrating that while mGluR1 and 5 may reside in close proximity to each other, and can interact functionally, this interaction does not appear to be due to canonical heterodimerization. Pharmacological evidence supporting this conclusion is largely pharmacological. To ask whether the observed interaction was due to a physical interaction between receptors rather than integration of signaling effects, mutations in each receptor were introduced that uncouple the receptors from G protein signaling, presumably without affecting ligand binding or associated conformational changes. We found that mGluR1 co‐expressed with a double point mutant of mGluR5, Y64A F768D (which right‐shifted the glutamate response and uncouple from G proteins, respectively), the glutamate response of mGluR1 was right shifted. When mGluR1Y74A, a mutant with a 300 fold right‐shifted response, was expressed with mGluR5 F768D, the response was left shifted. Expression of the signaling dead mGluR5 F768D with mGluR1 also altered the pharmacological sensitivity profile, causing mGluR1 to lose sensitivity to 3‐MATIDA and gain sensitivity to MPEP. Together, these findings support the hypothesis that allosteric interactions between the receptors are responsible for the observed functional interactions.Support or Funding InformationSupported by an institutional Drug Targets and Mechanisms pilot award.