Modulation of AMPA–type glutamate channels is important for synaptic plasticity. Here we provide physiological evidence that the activity of AMPA channels is regulated by protein phosphatase 1 (PP–1) in neostriatal neurons and identify two distinct molecular mechanisms of this regulation. One mechanism involves control of PP–1 catalytic activity by DARPP–32, a dopamine–and cAMP–regulated phosphoprotein highly enriched in neostriatum. The other involves binding of PP–1 to spinophilin, a protein that colocalizes PP–1 with AMPA receptors in postsynaptic densities. The results suggest that regulation of anchored PP–1 is important for AMPA–receptor–mediated synaptic transmission and plasticity.