G Protein-Coupled Glutamate and GABA Receptors Form Complexes and Mutually Modulate Their Signals

Molecular networks containing various proteins mediate many types of cellular processes. Elucidation of how the proteins interact will improve our understanding of the molecular integration and physiological and pharmacological propensities of the network. One of the most complicated and unexplained interactions between proteins is the inter-G protein-coupled receptor (GPCR) interaction. Recently, many studies have suggested that an interaction between neurotransmitter GPCRs may mediate diverse modalities of neural responses. The B-type gamma-aminobutyric acid (GABA) receptor (GBR) and type-1 metabotropic glutamate receptor (mGluR1) are GPCRs for GABA and glutamate, respectively, and each plays distinct roles in controlling neurotransmission. We have previously reported the possibility of their functional interaction in central neurons. Here, we examined the interaction of these GPCRs using stable cell lines and rat cerebella. Cell-surface imaging and coimmunoprecipitation analysis revealed that these GPCRs interact on the cell surface. Furthermore, fluorometry revealed that these GPCRs mutually modulate signal transduction. These findings provide solid evidence that mGluR1 and GBR have intrinsic abilities to form complexes and to mutually modulate signaling. These findings indicate that synaptic plasticity relies on a network of proteins far more complex than previously assumed.