Role of metabotropic glutamate receptors in CNS disorders

INTRODUCTION G protein-coupled receptors (GPCRs) have been one of the most studied, exploited, and lucrative therapeutic targets in modern neuroscience drug discovery efforts. GPCRs constitute the largest structural class of hormone and neurotransmitter receptors. The amino acid glutamate functions as the major excitatory neurotransmitter in the mammalian central nervous system (CNS). Its abundance and ubiquitous distribution throughout the brain highlights its importance in maintaining homeostatic functioning of the CNS and in the manifestation of brain disorders. The action of glutamate on cellular processes is mediated through a diverse family of glutamate receptors. These are broadly subdivided into the ionotropic and metabotropic glutamate receptors. Ionotropic receptors are multisubunit ion channels that mediate the rapid effects of glutmatergic neurotransmission through their opening and closing, altering the intracelullar ionic concentration. The metabotropic glutamate receptors (mGluRs) are typical members of the GPCR superfamily, which mediate their cellular effects by altering the concentrations of second messenger proteins. The GPCR superfamily is divided into three families based on sequence similarity, with mGluRs classified as family 3 GPCRs, which also includes GABA_B and certain pheromone receptors. The effects of mGluR activation are slower and longer lived than those of the ionotropic glutamate receptors, and allow the fine-tuning of the effects of glutamate at synapses in which ionotropic mediate a more rapid short-lived response. Although mGluRs mediate their effects through the altering of second messenger systems, their ultimate cellular influence can be diverse and wide-ranging, including regulation of ion channels, mediation of excitatory and inhibitory responses, and influencing the actions of other receptors such as ionotropic glutamate receptors.