Metabotropic glutamate receptors in peripheral tissues: implications for toxicology.

DURAND DANIELA; CARNIGLIA LILA; CARUSO CARLA; LASAGA MERCEDES

Anxiety Disorders

InTech - Open Access Publisher

Lugar: Rijeka; Año: 2011; p. 97 - 120

Glutamate, the main excitatory neurotransmitter in the central nervous system (CNS), signals through ionotropic receptors (iGluRs), including AMPA, kainate and NMDA receptors, which are glutamate-gated ion channels and regulate rapid responses upon activation, and metabotropic receptors (mGluRs), which evoke slower responses through activation of intracellular transduction cascades. mGluRs are single peptide seven-transmembrane spanning proteins linked to intracellular G-proteins although it has been reported that Gprotein- independent signalling can occur (Heuss et al., 1999). Eight different mGluRs (mGluR1–8) have been cloned and classified into three groups (groups I, II and III) based on sequence homology and the intracellular signal transduction pathways they activate. Group I metabotropic glutamate receptors include mGluR1 and mGluR5 subtypes, which activate phospholipase C and induce inositol triphosphate production and intracellular calcium mobilization. Group II mGluRs include mGluR2 and mGluR3 subtypes, whereas Group III mGluRs include mGluR4, mGluR6, mGluR7 and mGluR8 subtypes. All these receptors are negatively coupled to adenylyl cyclase signalling, resulting in inhibition of cyclic AMP production. Since mGluRs are expressed by neurons and glia near the synaptic cleft, where they modulate not only the effect of glutamate on the postsynaptic neurons but also the release of glutamate and other neurotransmitters, it is though that the mGluR system has evolved as a modulating mechanism for controlling excitability into the CNS (Schoepp, 2001). Furthermore, several mGluR subtypes were shown to exert glial and neuro-protective actions in distinct pathological conditions (Bruno et al., 1998; Kingston et al., 1999; D’Onofrio et al., 2001; Ciccarelli et al., 2007; Durand et al., 2010). However, mGluRs have currently received much attention motivated by a strong belief in their potential as drug targets for treatment of anxiety disorders and schizophrenia (Lavreysen & Dautzenberg, 2008; Chaki et al., 2010; Mezler et al., 2010; Schlumberger et al., 2009; Moreno et al., 2009; Patil et al., 2007). The strongest suggestion that mGluRs are not exclusively synaptic receptors derives from numerous studies that demonstrate the presence of functional mGluRs in a number of peripheral non-neuronal cells, many of which do not even originate from the neural crest (Nicoletti et al., 2007), shifting the role of these receptors from mere synaptic regulators to modulators of basic cell functions (such as cell proliferation, differentiation and survival) and key mediators of peripheral tissue function and neuroendocrine events. Besides organs that receive direct glutamatergic innervations, such as the heart and the adrenal glands, peripheral mGluRs can be activated in the absence of synaptic glutamate because of the existence of a large metabolic glutamate pool into cells derived from the Krebs cycle (Nicoletti et al., 2007). Then, metabolic glutamate can be transported outside the cell where it activates paracrine or autocrine mechanisms on cells expressing glutamate receptors. As implied by the evidence above, the use of selective mGluR agonists and antagonists as therapeutic agents in treatment of anxiety disorders rises the problem of undesirable side effects in these patients. Therefore, in an effort to warn against unsafeness of clinical trials in the area of the anxiety disorders, this chapter summarizes current knowledge of the distribution and actions of mGluRs outside the brain.