Glutamatergic receptors in parkinson's disease

Abstract

Extracellular concentrations of the excitatory glutamate are maintained at relatively low levels to avoid an excessive activation of glutamate receptors (GluRs) that can trigger a cell death. This neuronal loss induced by hyperexcitation of GluRs has been associated with a wide range of acute and chronic neurological disorders such as Parkinson's disease (PD). In fact, altered glutamatergic neurotransmission and metabolical dysfunction seems to be crucial in the pathophysiology of PD. Moreover, degeneration of dopamine nigral neurons of the substantia nigra pars compacta (SNpc) provokes striatal dopaminergic denervation and a cascade of functional modifications in the activity of basal ganglia nuclei including excitatory glutamate transmission. Glutamate receptors are divided into two distinct groups, ionotropic and metabotropic receptors. The ionotropic receptors (iGluRs) are further subdivided into three groups: (i) a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), (ii) kainate, and (iii) N-methyl-D-aspartate (NMDA) receptor channels. The metabotropic receptors (mGluRs) are coupled to GTP-binding proteins (G proteins) and regulate the production of intracellular messengers. In this chapter, we review recent progress in the research of GluRs with special emphasis on the molecular diversity of the mGluR system and its implications in the physiopathology of PD. Finally, based on these evidences, we highlight possible therapeutic strategies that might be important to slow down the progression of PD as well as to modulate levodopa-induced dyskinesias.