Regulation of NMDA channel function by endogenous Ca(2+)-dependent phosphatase

Area of Science:

• Neuroscience
• Molecular Biology
• Cellular Physiology

Background:

• Protein kinases regulate NMDA receptor activity.
• Phosphorylation/dephosphorylation of glutamate receptors influences neuronal excitability.
• The physiological control of NMDA channel phosphorylation cycles is not fully understood.

Purpose of the Study:

• To investigate the physiological control of NMDA channel phosphorylation cycles.
• To determine the role of endogenous phosphatases in regulating NMDA channel function.

Main Methods:

• Cell-attached patch-clamp recordings in acutely dissociated adult rat dentate gyrus granule cells.
• Application of phosphatase inhibitors (okadaic acid, FK506).
• Manipulation of calcium (Ca2+) entry through NMDA channels.

Main Results:

• Inhibitors of endogenous serine/threonine phosphatases prolonged NMDA channel opening duration, bursts, clusters, and superclusters.
• Okadaic acid's effect was dependent on calcineurin inhibition and Ca2+ entry.
• FK506, a calcineurin inhibitor, mimicked okadaic acid's effects.
• Calcineurin, activated by Ca2+ influx via NMDA channels, shortens NMDA channel opening duration.
• Phosphatase inhibition enhanced simulated synaptic currents.

Conclusions:

• Calcineurin, activated by NMDA channel Ca2+ influx, acts as a physiological regulator, shortening NMDA channel opening duration in adult neurons.
• Phosphorylation of the NMDA-receptor complex is crucial for short- and long-term control of neuronal excitability.