Beta-adrenergic regulation of synaptic NMDA receptors by cAMP-dependent protein kinase.

To identify the protein kinases regulating synaptic NMDA receptors, as well as the conditions favoring enhancement of NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) by phosphorylation, we studied the effects of kinase activation and inhibition in hippocampal neurons. Inhibition of cAMP-dependent protein kinase (PKA) prevented recovery of NMDA receptors from calcineurin-mediated dephosphorylation induced by synaptic activity, suggesting that tonically active PKA phosphorylates receptors during quiescent periods. Conversely, elevation of PKA activity by forskolin, cAMP analogs, or the beta-adrenergic receptor agonists norepinephrine and isoproterenol overcame the ability of calcineurin to depress the amplitude of NMDA EPSCs. Thus, stimulation of beta-adrenergic receptors during excitatory synaptic transmission can increase charge transfer and Ca2+ influx through NMDA receptors.