Modulation of the voltage-gated sodium current in rat striatal neurons by DARPP-32, an inhibitor of protein phosphatase.
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.
Schiffmann
S N
SN
Brain Research Unit, Université Libre de Bruxelles, Brussels, Belgium. sschiffm@ulb.ac.be
Desdouits
F
F
Menu
R
R
Greengard
P
P
Vincent
J D
JD
Vanderhaeghen
J J
JJ
Girault
J A
JA
D000818:Animals; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects*; D000242:Cyclic AMP / Q000494:pharmacology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015640:Ion Channel Gating; D008564:Membrane Potentials / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D019319:Okadaic Acid / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D010750:Phosphoproteins; D054645:Protein Phosphatase 1; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000187:drug effects; D015222:Sodium Channels / Q000187:drug effects*; D013779:Tetrodotoxin / Q000494:pharmacology
D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D017447:Receptors, Dopamine D1; D015222:Sodium Channels; D019319:Okadaic Acid; D013779:Tetrodotoxin; D000242:Cyclic AMP; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1