Phorbol ester pretreatment desensitizes the inhibition of Ca2+ channels induced by kappa-opiate, alpha 2-adrenergic, and muscarinic receptor agonists.
Acute treatment of rat spinal cord-dorsal root ganglion cocultured neurons with 12-O-tetradecanoylphorbol 13-acetate (TPA), a known activator of protein kinase C, inhibited the dihydropyridine-sensitive voltage-dependent 45Ca2+ influx measured in these cells (IC50 of approximately 100 nM, 66% inhibition at 1 microM TPA). However, prolonged preincubation (24 h) of the cells with 100 nM TPA followed by extensive washing completely abolished, i.e., desensitized, the capacity of a second application of TPA to inhibit the activity of the voltage-dependent Ca2+ channels. Moreover, this treatment also abolished the inhibition of Ca2+ influx produced by kappa-opiate as well as by alpha 2-adrenergic and muscarinic receptor agonists. Substantial desensitization was already observed following a 1-h pretreatment with 100 nM TPA. In contrast to TPA, an inactive phorbol ester (4 beta-phorbol 13-acetate) did not affect the inhibition of the voltage-dependent Ca2+ influx by these receptor agonists. These results suggest that protein kinase C may have a role in the modulation of Ca2+ channels by kappa-opiate, alpha 2-adrenergic, and muscarinic receptor agonists.
Attali
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Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.
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Vogel
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D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D002450:Cell Communication; D002478:Cells, Cultured; D003000:Clonidine / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000502:physiology*; D007700:Kinetics; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010095:Oxotremorine / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000502:physiology*; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D011957:Receptors, Opioid / Q000187:drug effects / Q000502:physiology*; D017450:Receptors, Opioid, mu; D013116:Spinal Cord / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D000700:Analgesics; D015220:Calcium Channels; D011759:Pyrrolidines; D011942:Receptors, Adrenergic, alpha; D011976:Receptors, Muscarinic; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D010095:Oxotremorine; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D003000:Clonidine; D013755:Tetradecanoylphorbol Acetate; D011188:Potassium; D002118:Calcium