The evidence for and consequences of metabotropic glutamate receptor heterodimerization

Abstract

Metabotropic glutamate receptors (mGluRs) are an essential component of the mammalian central nervous system. These receptors modulate neuronal excitability in response to extracellular glutamate through the activation of intracellular heterotrimeric G proteins. Like most other class C G protein-coupled receptors, mGluRs function as obligate dimer proteins, meaning they need to form dimer complexes before becoming functional receptors. All mGluRs possess the ability to homodimerize, but studies over the past ten years have demonstrated these receptors are also capable of forming heterodimers in specific patterns. These mGluR heterodimers appear to have their own unique biophysical behavior and pharmacology with both native and synthetic compounds with few rules having been identified that allow for prediction of the consequences of any particular mGluR pair forming heterodimers. Here, we review the relevant literature demonstrating the existence and consequences of mGluR heterodimerization. By collecting biophysical and pharmacological data of several mGluR heterodimers we demonstrate the lack of generalizable behavior of these complexes indicating that each individual dimeric pair needs to be investigated independently. Additionally, by combining sequence alignment and structural analysis, we propose that interactions between the β4-A Helix Loop and the D Helix in the extracellular domain of these receptors are the structural components that dictate heterodimerization compatibility. Finally, we discuss the potential implications of mGluR heterodimerization from the viewpoints of further developing our understanding of neuronal physiology and leveraging mGluRs as a therapeutic target for the treatment of pathophysiology.

Keywords: Class C GPCR; Heterodimer; Pharmacology; Sequence alignment; Structure analysis; mGluR.