Glutamate receptors constitute the principal excitatory neurotransmitter receptors in brain. Two classes of glutamate receptors exist: Ionotropic receptors, and metabotropic receptors (mGluRs). Metabotropic Glutamate Receptor 5b (GRM5) activity is mediated by a G-protein that activates a phosphatidylinositol-calcium second messenger system and generates a calcium-activated chloride current. The metabotropic glutamate receptor type 5 (mGlu5) is expressed in two splice variants, mGlu5a and mGlu5b, which differ in that mGlu5b has a 33-amino acid insert in the intracellular C-terminal domain. This receptor subtype is highly regulated, with higher levels found in developing animals.