Sigma1 receptor agonist-mediated regulation of N-methyl-D-aspartate-stimulated [3H]dopamine release is dependent upon protein kinase C.
We have previously shown that sigma1 receptor agonists inhibit N-methyl-D-aspartate (NMDA)-stimulated [3H]dopamine from slices of rat striatum in a concentration-related manner and that the inhibition is reversed by sigma1 receptor-selective and nonsubtype-selective sigma receptor antagonists. Based on previous evidence from our laboratory as well as other laboratories, we hypothesized that sigma1 receptors might use a protein kinase C (PKC) signaling pathway to modulate stimulated dopamine release. We tested several inhibitors of PKC isozymes, as well as a phospholipase C inhibitor for their effects on sigma1 receptor agonist-mediated regulation of [3H]dopamine release. Although none of the inhibitors tested affected the ability of NMDA to stimulate [3H]dopamine release, they all abolished regulation by the sigma1 receptor agonist (+)-pentazocine in a concentration-related manner. We also found that prior exposure to 1 microM phorbol 2-myristate 13-acetate for 30 min abolished regulation by (+)-pentazocine. We concluded that an intact PKC system was required for sigma1 agonist-mediated regulation of NMDA-stimulated [3H]dopamine release from rat striatal slices. Based on the pharmacological profile of the PKC inhibitors tested, as well as reports in the literature on PKC
Nuwayhid
Samer J
SJ
Department of Pharmacology, The George Washington University Medical Center, Washington, DC 20037, USA.
Werling
Linda L
LL
D000818:Animals; D004075:Diglycerides / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D010423:Pentazocine / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000819:agonists* / Q000037:antagonists & inhibitors; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors; D000097605:Sigma-1 Receptor
D004075:Diglycerides; D004298:Dopamine; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D007527:Isoenzymes; D016202:N-Methylaspartate; D009292:Narcotic Antagonists; D010423:Pentazocine; D011493:Protein Kinase C; D017480:Receptors, sigma; D013755:Tetradecanoylphorbol Acetate; D010738:Type C Phospholipases; D000097605:Sigma-1 Receptor