Role of Ionotropic Glutamate Receptors in Neurodegenerative and Other Disorders

Abstract

The central nervous system (CNS) plays host to some of the most unpredictable and complex disease states.While several hereditary and epigenetic factors play a role in neurodegenerative disorders, the last decade has seen a growing body of evidence for the role of ionotropic glutamate receptors. Synaptic dysfunction may be the primary mediators of neurodegeneration in Alzheimer’s and Parkinson’s disease. Because L-glutamate (L-Glu) is identified as the principal transmitter mediating fast excitatory synaptic responses, the roles that excitatory amino acids (EAA) play in neurotoxicity have increased. EAA receptors are arranged into two significant types – ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs). Within the CNS, the N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), and kainate subtype of ionotropic L-Glu receptors mediate post-synaptic Ca2+ influx. Excitotoxicity theories of neuronal degeneration suggest that L-Glu-mediated excitatory transmission can be transformed into mechanism that results in the selective destruction of neuronal cells. Localized excitotoxicity resulting from excessive activation of iGluRs may enhance the vulnerability of neurons in a manner consistent with the neuropathology seen in Alzheimer’s and Parkinson’s disease. This chapter will provide a detailed overview of the present status of research into iGluRs and their role in EAA-mediated excitotoxicity and neuronal degeneration in a number of pathological disease states.