σ2-receptor regulation of dopamine transporter via activation of protein kinase C

Document Type

Journal Article

Publication Date

4-6-2002

Journal

Journal of Pharmacology and Experimental Therapeutics

Volume

301

Issue

1

DOI

10.1124/jpet.301.1.306

Abstract

The elucidation of the mechanisms underlying σ2-receptor activation and signal transduction is crucial to the understanding of σ2-receptor function. Previous studies in our laboratory have demonstrated σ2-receptor-mediated regulation of the dopamine transporter (DAT) as measured by amphetamine-stimulated release of [3H]dopamine (DA) from both rat striatal slices and PC12 cells. The regulation of the DAT in the PC12 cell model was dependent upon activation of Ca2+/calmodulin-dependent kinase II. We have now studied the second messenger systems involved in σ2-receptor-mediated regulation of amphetamine-stimulated [3H]DA release in rat striatal slices, including Ca2+/calmodulin-dependent kinase II, protein kinase C, and sources of calcium required for the enhancement of release produced by σ2-receptor activation. The Ca2+/calmodulin-dependent kinase II inhibitors 1-[N,O-bis-(5-isoquionolinesulfonyl)]-N-methyl-L-tyrosyl-4-phenylpiperazine and N-[2-[[[3-(4′-chlorophenyl)-2-propenyl]methylamino] methyl]-phenyl]-N-(2-hydroxyethyl)-4′-methoxy-benzenesulfonamide phosphate did not significantly affect the (+)-pentazocine-mediated enhancement of amphetamine-stimulated [3H]DA release. However, we found that an inhibitor of protein kinase C, 3-[1-[3-(dimethylamino)propyl]-1H-indol-3-yl)-1H-pyrrole-2,5-dione, blocks the (+)-pentazocine-mediated enhancement in rat striatal slices. The protein kinase C activator phorbol 12-myristate 13-acetate, but not the inactive isophorbol 4α,9α,12α,13α,20-pentahydroxytiglia-1,6-dien-3-one, enhanced the amphetamine-stimulated [3H]DA release comparable to the enhancement seen by (+)-pentazocine alone. Additionally, the L-type voltage-dependent calcium channel inhibitor nitrendipine or prior treatment with thapsigargin, but not the N-type voltage-dependent calcium channel ω-conotoxin MVIIA, attenuated the (+)-pentazocine-mediated enhancement. Together, these data suggest that activation of σ2-receptors results in the regulation of DAT activity via a calcium- and protein kinase C-dependent signaling mechanism.

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