Page - (000180) - in Biomedical Chemistry: Current Trends and Developments

independent ion channels and permeable to Na+ and K+, leading to a net depolarizing influx of cations upon activation by glutamate (Swanson, 1997). AMPA receptors are composed of four possible subunits, GluA1-4, which associate in different stoichiometries to form receptors with distinct properties (Greger, 2007). NMDA receptors are ligand-gated ion channels that exhibit strong voltage dependence owing to the blocking of the receptor channels at negative membrane potentials by extracellular magnesium. As a result, these receptors contribute little to the postsynaptic response during low-frequency synaptic activity. However, when the cell is depolarized, Mg2+ dissociates from its binding site within the NMDAR channel, allowing Ca2+ and Na+ to enter the dendritic spine (Cull-Candy, 2001). Functional NMDA receptors are heterotrimeric complexes containing both GluN1 and GluN2 subunits (Prybylowski, 2004). Metabotropic glutamate receptors are coupled to G proteins (which in turn stimulate second messenger signaling pathways), and, as such, they mediate slower synaptic responses, occurring over seconds and minutes, rather than milliseconds as occurs for ionotropic glutamate receptors. There are three groups of mGluR, distinguished based on sequence homology, signal transduction mechanisms and agonist selectivity (Pin, 2002; Kim, 2008; Niswender, 2010). Glutamatergic neurons play crucial roles in physiological mechanisms, such as synaptic plasticity mechanism like long-term potentiation (LTP) and long-term depression (LTD) underlying processes of learning and memory. However, disturbances in glutamatergic signaling contribute to the pathogenesis of several neurological disorders, such as ischemic stroke, schizophrenia, epilepsy and neurodegenerative disorders (Dong, 2009; Szydlowska, 2010). Neuronal excitotoxicity refers to the injury of neurons resulting from a prolonged exposure to glutamate and consequent overactivation of both ionotropic and metabotropic glutamate receptors (Choi, 1988; Kroemer, 2009). The associated sustained influx of ions into neurons, and particularly, calcium overload through NMDA receptors and calcium release from intracellular stores triggered by mGluRs is highly neurotoxic, leading to the activation of enzymes that will degrade membranes, proteins, and nucleic acids, which ultimately lead to cell death (Friedman, 2006;