Art - Greengard (E)

The neostriatum is critically involved in the control of movement. The activity of neostriatal neurons is regulated by two major inputs: a glutamatergic input from the cortex and a dopaminergic input from the substantia nigra. Ionotropic glutamate receptors mediate synaptic transmission and plasticity in the neostriatum through intrinsic ligand-gated ion channels. In contrast, dopamine receptors modulate the excitability of neostriatal neurons by coupling to G-protein pathways. An understanding of the functional interactions between glutamate and dopamine systems in the neostriatum would have considerable clinical significance, because imbalances in dopaminergic and glutamatergic synaptic transmission have been implicated in several neurological disorders, including Parkinson’s disease, Huntington’s disease and schizophrenia1–3. Ionotropic glutamate receptors are classified as AMPA receptors, kainate receptors or NMDA receptors, based on their physiological and pharmacological properties. Each of these ligand-gated channels is an oligomeric complex composed of different subunits4,5. Functional AMPA receptors and NMDA receptors have been found in basal ganglion neurons6. Stimulation of corticostriatal fibers can induce AMPA-receptor-mediated long-term depression (LTD) in neostriatum7,8. Changes in postsynaptic AMPA receptors have been implicated in synaptic plasticity9–11, but the underlying molecular mechanisms for the regulation of AMPA channels are unclear. One potential mechanism is alteration of the phosphorylation state of AMPA receptors. Protein kinase A (PKA) and calcium/calmodulin-dependent kinase II (CaMKII) potentiate AMPA receptor currents in hippocampal neurons12–14, but the specific protein phosphatase responsible for the modulation of AMPA channels has not been identified13. High levels of dopamine receptors are found in neostriatal neurons15,16. Dopamine receptors are grouped into two classes: D1-class (D1, D5) and D2-class (D2, D3, D4), based on their distinct pharmacological properties and signaling cascades. Activation of different dopamine receptors modulates a variety of voltage-dependent and ligand-gated channels in neostriatum17–19. Glutamatergic transmisson is regulated by dopamine in neostriatal neurons20. However, the signaling pathways mediating dopaminergic modulation of glutamate channels remain to be elucidated. In neostriatum, activation of D1 receptors elevates PKA activity and increases the phosphorylation of DARPP-32, a dopamineand cAMP-regulated phosphoprotein highly enriched in all dopamine-innervated neurons21. DARPP-32, in its phosphorylated but not dephosphorylated form, acts as a potent inhibitor of protein phosphatase 1 (PP-1)22. PP-1 is localized to postsynaptic densities23, presumably through association with spinophilin, a novel PP-1-binding protein, which is highly enriched in dendritic spines24. The present study provides physiological and biochemical evidence that AMPA channels are modulated by PP-1 and that this modulation occurs through at least two distinct mechanisms. One mechanism involves the dopamine-induced phosphorylation of DARPP-32, inhibition of PP-1 activity and an increase in the phosphorylation state of AMPA channels. The second mechanism involves spinophilin-mediated anchoring of PP-1 to postsynaptic densities and facilitated dephosphorylation of AMPA channels.