Therapeutic potential of metabotropic glutamate receptor modulators

Abstract

Glutamate is the main excitatory neurotransmitter in the central nervous system (CNS) and is a major player in complex brain functions. Glutamatergic transmission is primarily mediated by ionotropic glutamate receptors, which include NMDA, AMPA and kainate receptors. However, glutamate exerts modulatory actions through a family of metabotropic G-protein-coupled glutamate receptors (mGluRs). Dysfunctions of glutamatergic neurotransmission have been implicated in the etiology of several diseases. Therefore, pharmacological modulation of ionotropic glutamate receptors has been widely investigated as a potential therapeutic strategy for the treatment of several disorders associated with glutamatergic dysfunction. However, blockade of ionotropic glutamate receptors might be accompanied by severe side effects due to their vital role in many important physiological functions. A different strategy aimed at pharmacologically interfering with mGluR function has recently gained interest. Many subtype selective agonists and antagonists have been identified and widely used in preclinical studies as an attempt to elucidate the role of specific mGluRs subtypes in glutamatergic transmission. These studies have allowed linkage between specific subtypes and various physiological functions and more importantly to pathological states. This article reviews the currently available knowledge regarding the therapeutic potential of targeting mGluRs in the treatment of several CNS disorders, including schizophrenia, addiction, major depressive disorder and anxiety, Fragile X Syndrome, Parkinson's disease, Alzheimer's disease and pain.

Keywords: Addiction; Huntington’s disease; Parkinson’s disease; alzheimer’s disease; anxiety; depression; epilepsy; fragile X syndrome; metabotropic glutamate receptors; pain; schizophrenia..

Fig. (1)

Intracellular signalling pathways associated to the different mGluR subtypes. Group I mGluRs, including mGluR1 and mGluR5, are positively coupled to phospholipase C (PLC) through activation of a G-protein of the G_q type; in turn, production of innositol triphosphate (IP3), release of Ca²⁺ from intracellular stores and production of diacylglycerol (DAG) activate protein kinase C. Group II and Group III mGluRs are negatively coupled to adenylate cyclase (AC) through G-protein of the G_i/G_o type, leading to decreased formation of cyclic AMP (cAMP).

Fig. (2)

Subcellular localization of the different mGluR subtypes in the glutamatergic synapse. Group I mGluRs, including mGluR1 and mGluR5, are almost exclusively located post-synaptically, and mGluR5 are present both synaptically and extrasynaptically. Group II mGluRs are predominantly located on presynaptic terminals in the extrasynaptic space, with the exception of mGluR3 which is highly expressed on glial cells as well as postsynaptically. Group III mGluRs are also principally expressed presynaptically; interestingly, mGluR7 is located in the synaptic cleft while mGluR4 and 8 are mostly extrasynaptic. Note that mGluR3 and mGluR7 are also present on non-glutamatergic (e.g. GABAergic) terminals.