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Effects of κ‐opioid receptor stimulation in the heart and the involvement of protein kinase C
Author(s) -
Bian JinSong,
Wang HongXin,
Zhang WeiMin,
Wong TakMing
Publication year - 1998
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701857
Subject(s) - chelerythrine , protein kinase c , staurosporine , forskolin , agonist , endocrinology , medicine , chemistry , stimulation , phorbol , receptor antagonist , receptor , antagonist , pharmacology , biology , kinase , biochemistry
The role of protein kinase C (PKC) in mediating the action of κ‐receptor stimulation on intracellular Ca 2+ and cyclic AMP production was determined by studying the effects of trans ‐(±)‐3,4‐dichloro‐N‐methyl‐N‐(2‐[1‐pyrrolidinyl] cyclohexyl) benzeneacetamide methanesulphonate (U50,488H), a selective κ‐receptor agonist, and phorbol 12‐myristate 13‐acetate (PMA), a PKC agonist, on the electrically‐induced [Ca 2+ ] i transient and forskolin‐stimulated cyclic AMP accumulation in the presence and absence of a PKC antagonist, staurosporine or chelerythrine, in the single rat ventricular myocyte. U50,488H at 2.5–40 μ M decreased both the electrically‐induced [Ca 2+ ] i transient and forskolin‐stimulated cyclic AMP accumulation dose‐dependently, effects which PMA mimicked. The effects of the κ‐agonist, that were blocked by a selective κ‐antagonist, nor‐binaltorphimine, were significantly antagonized by the PKC antagonists, staurosporine and/or chelerythrine. The results indicate that PKC mediates the actions of κ‐receptor stimulation. To determine whether the action of PKC was at the sarcoplasmic reticulum (SR) or not, the [Ca 2+ ] i transient induced by caffeine, that depletes the SR of Ca 2+ , was used as an indicator of Ca 2+ content in the SR. The caffeine‐induced [Ca 2+ ] i transient was significantly reduced by U50,488H at 20 μ M . This effect of U50,488H on caffeine‐induced [Ca 2+ ] i transient was significantly attenuated by 1 μ M chelerythrine, indicating that the action of PKC involves mobilization of Ca 2+ from the SR. When the increase in IP 3 production in response to κ‐receptor stimulation with U50,488H in the ventricular myocyte was determined, the effect of U50,488H was the same in the presence and absence of staurosporine, suggesting that the effect of PKC activation subsequent to κ‐receptor stimulation does not involve IP 3 . The observations suggest that PKC may act directly at the SR. In conclusion, the present study has provided evidence for the first time that PKC may be involved in the action of κ‐receptor stimulation on Ca 2+ in the SR and cyclic AMP production, both of which play an essential role in Ca 2+ homeostasis in the heart.