Modulation of NMDA Receptor Current by Protein Kinase C: Molecular and Synaptic Studies

点击翻译按钮获取中文摘要

Glutamate is the most abundant neurotransmitter that brain cells use to trigger electrical impulses in other brain cells they contact. At these sites of contact, called synapses, many vital processes take place. There are many different types of receptors for glutamate encoded by different gene families, which have different specific actions at synapses. The NMDA family of glutamate receptors is of particular importance because they can trigger changes in the level of sensitivity of synaptic connections between brain cells. Modulation by enzymes called kinases adds phosphate chemical groups to NMDA receptors causing marked enhancement of current passing through these receptors and enhancing signaling between brain cells. This modulatory effect has an important role in processes related to learning, development, and degeneration of brain cells. The identification of the sites on NMDA receptor subunits targeted by specific kinases will provide research tools for studying the physiological importance of NMDA receptor phosphorylation in brain cells. In the case of modulation by protein kinases of the C-type (PKC), the presence of these sites may also depend on the particular NMDA receptor family member present. In a particularly exciting example of the importance of NMDA receptor subtype, the NMDA receptor subunit that is more prevalent in young brains, NR2B, has been shown to give rise to more easily modifiable synaptic connections. Receptors that contain NR2B subunits pass larger calcium ion currents than other NMDA receptors. The present proposal hypothesizes that this difference is due to an increased sensitivity to PKC. Controlled expression of selectively mutated NMDA receptors in my laboratory has recently demonstrated that direct phosphorylation of 2 specific serine amino acid sites (S1303 and S1323) by protein kinase C controls current amplification in NR2B receptors. This result motivates the aims of the proposal and: 1) challenges a previous viewpoint that kinase modulation of current must be entirely indirect via other proteins associated with NMDA receptors at the synapse, and 2) provides a starting point for elucidating a mechanism of direct kinase action. These studies uniquely focus on modulation of the NMDA current that itself triggers long-term synaptic changes in brain cells.