Agonist-independent activation of metabotropic glutamate receptors by the intracellular protein Homer

G-protein-coupled receptors (GPCRs) transduce signals from extracellular tr ansmitters to the inside of the cell by activating G proteins. Mutation and overexpression of these receptors have revealed that they can reach their active state even in the absence of agonist, as a result of a natural shift in the equilibrium between their inactive and active conformations(1). Suc h agonist-independent (constitutive) activity has been observed for the glu tamate GPCRs (the metabotropic glutamate receptors mGluR1a and mGluR5) when they are overexpressed in heterologous cells(2). Here we show that in neur ons, the constitutive activity of these receptors is controlled by Homer pr oteins, which bind directly to the receptors' carboxy-terminal intracellula r domains(3,4). Disruption of this interaction by mutagenesis or antisense strategies, or expression of endogenous Homer1a (H1a), induces constitutive activity in mGluR1a or mGluR5. Our results show that these glutamate GPCRs can be directly activated by intracellular proteins as well as by agonists .