Regulation of NMDA Receptors by Kinases and Phosphatases

Phosphorylation is a fundamental and pervasive mechanism widely known to regulate the functions of proteins [94,133], and lipids [8]. Phosphorylation of specific amino acid residues is a reversible process controlled enzymatically by the competing activities of protein kinases that catalyze phosphorylation and phosphoprotein phosphatases that catalyze dephosphorylation. Several years before the cloning of glutamate receptors, phosphorylation was found to increase NMDA currents, and dephosphorylation to decrease these currents in neurons from the hippocampus [76]. Since then, two principal protein kinase/phosphatase families have been studied extensively related to regulation of NMDA receptors (NMDARs) in the central nervous system: those that act at serine/threonine residues and those that act at tyrosine residues. Phosphorylation and dephosphorylation may regulate the gating or cell surface expression of NMDARs. Recently, an additional mechanism, alteration of the relative permeability of the NMDAR channel to Ca, has been suggested to be subject to regulation by phosphorylation [112]. The simplest biochemical event that may under-lie the regulation of NMDARs is phosphorylation of a single amino acid in one of the core NR subunit proteins. This phosphorylation may then be reversed by the action of phosphoprotein phosphatase, and thus the relative levels of phosphorylation and dephosphorylation are determined by the competing actions of those enzymes, i.e., those that are most proximate in the regulatory pathways. While such direct phosphorylation on serine/threonine and tyrosine residues has been demonstrated, whether such phosphorylation alone is necessary or sufficient for the subsequent increase in NMDAR currents is not known definitively and remains an open question. Alternative mechanisms that are nearly as simple, such as phosphorylation of regulatory or trafficking proteins in NMDAR complexes or of cytoskeletal or other elements also may contribute to changes in NMDAR currents. The kinase and phosphatase enzymes most proximate in the regulatory control of NMDARs are typically held within NMDAR complexes through anchoring proteins (Figure 7.1) that allow the strategic localization of each enzyme in proximity to its substrate in the complex. This may enhance the efficiency and specificity of the signaling pathways. Based on the key role of NMDARs in many forms of synaptic plasticity, that signaling complexes containing both kinases and their counterpart phosphatases are specifically targeted to the receptor complex facilitates bidirectional regulation of NMDARs during synaptic plasticity. Moreover, these enzymes are also subject to complex regulation by intracellular biochemical signaling networks, leading to multiple levels of control that are dynamic in time and space in certain neurons. Adding to the complexity, the enzymes regulating NMDARs may be differentially expressed in different neuronal populations in the CNS, and the expression may change during development or under physiological or pathological conditions. This chapter provides an overview of the current state of knowledge about NMDAR regulation by serine/threonine and tyrosine phosphorylation, and the cross-talk between these kinase/phosphatase signaling pathways.