GPCR interactions involving metabotropic glutamate receptors and their relevance to the pathophysiology and treatment of CNS disorders.

Cellular responses to metabotropic glutamate (mGlu) receptor activation are shaped by mechanisms of receptor-receptor interaction. mGlu receptor subtypes form homodimers, intra- or inter-group heterodimers, and heteromeric complexes with other G protein-coupled receptors (GPCRs). In addition, mGlu receptors may functionally interact with other receptors through the βγ subunits released from G proteins in response to receptor activation or other mechanisms. Here, we discuss the interactions between (i) mGlu and GABA receptors in cerebellar Purkinje cells; (ii) mGlu and 5-HTserotonergic receptors in the prefrontal cortex; (iii) mGlu and A receptors or mGlu and D dopamine receptors in medium spiny projection neurons of the indirect and direct pathways of the basal ganglia motor circuit; (iv) mGlu and A receptors in relation to the pathophysiology of Alzheimer's disease; and (v) mGlu and A adenosine or α- or β adrenergic receptors. In addition, we describe in detail a novel form of non-heterodimeric interaction between mGlu and mGlu receptors, which appears to be critically involved in mechanisms of activity-dependent synaptic plasticity in the prefrontal cortex and hippocampus. Finally, we highlight the potential implication of these interactions in the pathophysiology and treatment of cerebellar disorders, schizophrenia, Alzheimer's disease, Parkinson's disease, l-DOPA-induced dyskinesias, stress-related disorders, and cognitive dysfunctions. This article is part of the Special Issue on "The receptor-receptor interaction as a new target for therapy".