DARPP-32 is a cyclic adenosine monophosphate-regulated inhibitor of protein phosphatase 1, highly enriched in striatonigral neurons. Stimulation of dopamine D1 receptors increases phosphorylation of DARPP-32, whereas glutamate acting on N-methyl-D-aspartate receptors induces its dephosphorylation. Yet, to date, there is little direct evidence for the function of DARPP-32 in striatal neurons. Using a whole cell patch-clamp technique, we have studied the role of DARPP-32 in the regulation of voltage-gated sodium channels in rat striatal neurons maintained in primary culture. Injection of phospho-DARPP-32, but not of the unphosphorylated form, reduced the sodium current amplitude. This effect was similar to those induced by okadaic acid, with which there was no additivity and by tautomycin. Our results indicate that, in striatal neurons, sodium channels are under dynamic control by phosphorylation/dephosphorylation, and that phospho-DARPP-32 reduces sodium current by stabilizing a phosphorylated state of the channel or an associated regulatory protein. We propose that the DARPP-32-mediated modulation of sodium channels, via inhibition of phosphatase 1, contributes to the regulation of these channels by D1 receptors and other neurotransmitters which influence the state of phosphorylation of DARPP-32.
Two dog adenosine receptors have been recently cloned. They were pharmacologically characterized as an A, and the A, , receptor, respectively. The adenosine A,, receptor i s exclusively expressed in medium-sized neurons of the striatum as demonstrated by in situ hybridization. The relationships of this A, , receptor with three major components of the striaturn, enkephalin, substance P, and choline acetyltransferase, were studied in the rat. This demonstrates that the adenosine A2, receptor i s exclusively expressed by the enkephalinergic striatal neuronal subpopulation that also selectively expresses the dopamine D2 receptor. Conversely, the A, , receptor i s never detected in the substance P containing neurons or in the cholinergic neurons. This observation most probably constitutes the anatomical substratum for the previously described A2,-D2 receptors interactions. It also indicates that A, , receptor is selectively express in the indirect pathway of the basal ganglia system which is hypoactive in hyperkinetic disorders such as Huntington's disease and hyperactive in hypokinetic disorders such as Parkinson's disease. The development of highly A, , selective ligands could be therefore useful in the therapy of basal ganglia degenerative diseases. o 1993 Wiley-Liss, Inc.
The microtubule-associated protein tau favors microtubule nucleation and stabilization and plays a role in the elongation of axons. We have investigated the ability of glycogen synthase kinase-3L L (GSK-3L L) to control tau-induced processes outgrowth. Tau-transfected Chinese hamster ovary (CHO) cells developed processes containing microtubule bundles after cytochalasin treatment, but a significant reduction in the number of cells harboring processes was observed in tau/GSK-3L L-cotransfected cells. Lithium, an inhibitor of GSK-3L L, counteracted in a dose-dependent manner this inhibitory effect of GSK-3L L. These findings suggest that GSK-3L L modulates in a graded manner the ability of tau to control the microtubule-dependent induction of cell processes.z 2000 Federation of European Biochemical Societies.
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