Imaging of Metabotropic Glutamate Receptors (mGluRs)

Abstract

The ubiquitous amino acid L-glutamate is thought to act as a neurotransmitter at the majority of synapses in the brain. It mediates the major excitatory pathways in the brain, and is referred to as an excitatory amino acid (EAA). The EAA plays a role in a variety of physiological processes, such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation, emotional states and sensory perception (Bliss & Collingridge, 1993). The excessive or inappropriate stimulation of EAA receptors leads to neural cell damage or loss by a mechanism known as excitotoxicity (Lucas & Newhouse, 1957; Oney, 1978). EAA receptors are classified in two general types (Kornhuber & Weller, 1997). Receptors that are directly coupled to the opening of cation channels in the cell membranes of the neuron are termed ‘ionotropic’, which include NMDA, AMPA, and kainate receptors. The second type of receptors are the G-protein or second messenger-linked ‘metabotropic’ EAA receptors. This second type is coupled to multiple second messenger systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D, increase or decrease in cAMP formation, and changes in ion channel function (Kozikowski et al., 1998). Metabotropic glutamate receptors belong to Class C of a superfamily of G-protein coupled receptors (GPCRs). Class C GPCRs possess a large extracellular domain that is responsible for endogenous ligand recognition (Pin et al., 2003), in addition to the seven strand transmembrane domain, which is characteristic of all GPCRs. The mGluRs possess a large bi-lobed extracellular N-terminus of ~560 amino acids which has been shown by mutagenesis studies to confer glutamate binding, agonist activation of the receptor, and subtype specificity for group selective agonists (Schoepp et al., 1999). Since mGluRs have neuromodulatory role in the control of both glutamatergic and GABAergic neurotransmission, there has been much interest to develop novel mGluR ligands for therapeutic purposes of a variety of neurological and psychiatric conditions. The mGluRs have been proposed to be involved in physiological and pathophysiological processes of a number of CNS disorders, including anxiety, pain, depression, neurodegenerative disorders, schizophrenia, epilepsy, and drug abuse. In order to