Page - (000279) - in Biomedical Chemistry: Current Trends and Developments

NMDA receptors have slow gating kinetics, but once open, are highly permeable to both calcium and sodium. Because of the large ion permeability to calcium, this influx generates intracellular calcium waves or transients (also the term “calcium spikes” is popular in the literature) that set off myriad calcium-mediated biochemical cascades. The NMDA receptors are bound to postsynaptic cytoskeletal scaffolding proteins that are collectively known as the postsynaptic density. This scaffolding also supports kinases and other proteins that have downstream signaling roles, likely to receive the calcium transient as efficiently as possible. Under normal circumstances, glutamate is quickly removed from the synaptic cleft by excitatory amino acid transporters (EAAT) located on nearby glial cells. This ensures that only a limited amount of calcium will be able to enter the postsynaptic neuron. 3.2.3 The Role of Calcium in Normal Neuronal Biochemistry NMDA receptors are opened when the neuronal membrane potential is depolarized to a sufficient level to expel the bound magnesium ion. Opening of these ionotropic receptors leads to a rise in postsynaptic calcium concentration, which has been linked to long-term potentiation (LTP) via protein kinase activation. It is thought that strong depolarization fully expels the magnesium plug, whereas milder depolarization partially displaces the magnesium, resulting in less access to calcium through NMDA receptors. This latter process is thought to underlie long-term depression (LTD), in which lower concentrations of postsynaptic calcium activates protein phosphatases and initiates partial dismantling of the synaptic connection. The activated protein kinases that arise from the high calcium concentration phosphorylate a variety of postsynaptic targets including some AMPA receptors. These post-translational modifications have been shown to enhance single channel conduction through these channels, thereby potentiating the connection between these two neurons. Further, these kinases can phosphorylate the protein machinery that determines the number of postsynaptic AMPA receptors, thus opening