Phosphorylation of glutamate receptors: a potential mechanism for the regulation of receptor function and psychostimulant action.

Ionotropic glutamate receptors, N-methyl-d-aspartate receptors (NMDARs) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs), are densely distributed in the mammalian brain and actively regulate a variety of cellular activities. Expression and function of these receptors are also under a tight regulation by many molecular mechanisms. Protein phosphorylation represents one of the important mechanisms for the posttranslational modulation of these receptors. Constitutive and regulatory phosphorylation occurs at distinct sites (serine, threonine, or tyrosine) on the intracellular C-terminal domain of almost all subunits capable of assembling a functional channel. Several key protein kinases, such as protein kinase A, protein kinase C, Ca(2+)/calmodulin-dependent protein kinases, and tyrosine kinases are involved in the site-specific catalyzation and regulation of NMDAR and AMPAR phosphorylation. Through the phosphorylation mechanism, these protein kinases as well as protein phosphatases control biochemical properties (biosynthesis, delivery, and subunit assembling), subcellular distribution, and interactions of these receptors with various synaptic proteins, which ultimately modify the efficacy and strength of excitatory synapses containing NMDARs and AMPARs and many forms of synaptic plasticity. Emerging evidence shows that psychostimulants (cocaine and amphetamine) are among effective agents that profoundly alter the phosphorylation status of both receptors in striatal neurons in vivo. Thus, psychostimulants may modulate NMDAR and AMPAR function through the phosphorylation mechanism to shape the excitatory synaptic plasticity related to additive properties of drugs of abuse.