Glutamate Cascade from Metabotropic Glutamate Receptors to Gene Expression in Striatal Neurons

Glutamate is a major excitatory neurotransmitter in the central nervous system (CNS), which regulates a variety of neuronal activities through interaction with glutamate receptors. Glutamate receptors are divided into two major families: ionotropic (ligand-gated ion channels) and metabotropic (G-protein coupled) receptors based on their biochemical, pharmacological, and molecular profiles (1). Compared to thoroughly investigated roles of the ionotropic receptors, functional studies on metabotropic glutamate receptors (mGluRs) are just emerging in recent years. At present, eight subtypes of mGluRs (mGluR1–8) have been cloned from rat brain tissues. Like ionotropic receptors, mGluR subtypes are heterogeneous in their distribution, pharmacology, and connections with intracellular effectors. According to their sequence homology, pharmacology, and intracellular responses to activation of the mGluRs expressed in the Xenopus oocyte system, the eight subtypes are currently classified into three functional groups (2). Activation of group I mGluRs (mG1uR1/5) increases phosphoinositide (PI) hydrolysis via stimulation of phospholipase C, resulting in the subsequent Ca2+ release from internal stores and protein kinase C activation. Activation of group II (mGluR2/3) and group III (mGluR4/6/7/8) mGluRs inhibits the adenylyl cyclase and cAMP formation in an adenylate cyclasedependent fashion. The linkages to diverse intracellular effectors, such as cAMP and Ca2+, allow mGluRs to be vigorously involved in the slower effects in intracellular and intranuclear compartments, such as DNA transcription (gene expression), as opposed to rapid signal transmission in synapses mediated by ionotropic glutamate receptors.