Page - (000275) - in Biomedical Chemistry: Current Trends and Developments

number of congenital and sporadic neurodegenerative disorders such as Alzheimer’s, stroke, Huntington’s, Parkinson’s, Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS). Receptors located at the neuronal membrane help regulate these fluctuations in membrane potential by controlling the opening and closing of transmembrane ion channels, which variously allow cations and anions to flow into and out of the neuron down their electrical and chemical concentration gradient. During typical communication at an excitatory synapse, the presynaptic cell releases glutamate, the primary excitatory neurotransmitter, after an influx of calcium that enters through voltage-gated calcium channels. Glutamate crosses the synaptic cleft by diffusion and binds to receptors on the postsynaptic cell. Some glutamate receptors are ionotropic ligand-gated channels that are found on the postsynaptic neuron. When an agonist such as glutamate binds, the associated ion channel opens, allowing monovalent cations, primarily sodium, to flow into the neuron. As the positive charge flows into the neuron, the membrane potential of that postsynaptic cell depolarizes, and if it is sufficiently depolarized, other receptors located nearby on the membrane will open as well, eventually allowing calcium to enter the postsynaptic cell. Glutamate is the most prevalent excitatory neurotransmitter in the central nervous system (CNS) and glutamate receptors (GluRs) play a key role in both normal excitatory neurotransmission, and in modulating both normal and constructive plasticity as well as excitotoxic biochemistry, the main topic of this chapter (Cotman & Monaghan, 1986; Debelleroche & Bradford, 1977; Moore & Buchanan, 1993). There are two major types of GluRs that differ in the way they influence neuronal response to excitatory neurotransmission. The first are the metabotropic glutamate receptors (mGluRs) which, upon binding to glutamate, set off an intracellular biochemical cascade via second messenger signaling. While mGluRs are certainly targets of interest for negating the excitotoxic effects of over-stimulation, they are not the focus of this work, however, a well-written and expansive review of mGluRs and pharmacological agents was published recently (Williams & Dexter, 2014). Of more importance here, ionotropic glutamate receptors (iGluRs) mediate fast responses to glutamate release and also, as their