Control of constitutive activity of metabotropic glutamate receptors by Homer proteins

The postsynaptic metabotropic glutamate receptor subtypes 1a and 5 (mGluR1a and mGluR5) control excitatory synaptic transmission in the mammalian brain. These receptors are coupled to inositol trisphosphate- and ryanodine-sensitive Ca²⁺ stores via G proteins. The scaffolding protein Homer1b, Homer1c, Homer2, or Homer3 physically links mGluR1a or mGluR5 to these intracellular Ca²⁺ stores. The short splice variant Homer1a represents an exception within the family of Homer proteins. This protein is the product of an immediate early gene induced after intense neuronal activity that disrupts the mGluR1a/5–Ca²⁺ store scaffold. In the absence of agonist, Homer3 stabilizes mGluR1a and mGluR5 in an inactivate state, whereas Homer1a competes with Homer3 on mGluR1a and mGluR5, and directly activates these receptors. This is the first evidence showing that an intracellular protein can induce a constitutive activity of a G protein-coupled receptor, in response to intrinsic neuronal activity.