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. 1995 Nov;116(6):2603–2610. doi: 10.1111/j.1476-5381.1995.tb17214.x

Characterization of inhibition by haloperidol and chlorpromazine of a voltage-activated K+ current in rat phaeochromocytoma cells.

K Nakazawa 1, K Ito 1, S Koizumi 1, Y Ohno 1, K Inoue 1
PMCID: PMC1909140  PMID: 8590977

Abstract

1. Inhibition by haloperidol and chlorpromazine of a voltage-activated K+ current was characterized in rat phaeochromocytoma PC12 cells by use of whole-cell voltage-clamp techniques. 2. Haloperidol or chlorpromazine (1 and 10 microM) inhibited a K+ current activated by a test potential of +20 mV applied from a holding potential of -60 mV. The K+ current inhibition did not exhibit voltage-dependence when test potentials were changed between -10 and +40 mV or when holding potentials were changed between -120 and -60 mV. 3. Effects of compounds that are related to haloperidol and chlorpromazine in their pharmacological actions were examined. Fluspirilene (1 and 10 microM), an antipsychotic drug, inhibited the K+ current, but pimozide (1 and 10 microM), another antipsychotic drug did not significantly inhibit the K+ current. Sulpiride (1 or 10 microM), an antagonist of dopamine D2 receptors, did not affect the K+ current whereas (+)-SCH-23390 (10 microM), an antagonist of dopamine D1 receptors, reduced the K+ current. As for calmodulin antagonists, W-7 (100 microM), but not calmidazolium (1 microM), reduced the K+ current. 4. The inhibition by haloperidol or chlorpromazine of the K+ current was abolished when GTP in intracellular solution was replaced with GDP beta S. Similarly, the inhibition by pimozide, fluspirilene, (+)-SCH-23390 or W-7 was abolished or attenuated in the presence of intracellular GDP beta S. The inhibition by haloperidol or chlorpromazine was not prevented when cells were pretreated with pertussis toxin or when K-252a, an inhibitor of a variety of protein kinases, was included in the intracellular solution. 5. Haloperidol and chlorpromazine reduced a Ba2+ current permeating through Ca2+ channels. Inhibition by haloperidol or chlorpromazine of the Ba2+ current was not affected by GDP beta S included in the intracellular solution. 6. It is concluded that haloperidol and chlorpromazine inhibit voltage-gated K+ channels in PC12 cells by a mechanism involving GTP-binding proteins. The inhibition may not be related to their activity as antagonists of dopamine D2 receptors or calmodulin antagonists.

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Selected References

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  1. Brown D. A. M currents. Ion Channels. 1988;1:55–94. doi: 10.1007/978-1-4615-7302-9_2. [DOI] [PubMed] [Google Scholar]
  2. Choi J. J., Huang G. J., Shafik E., Wu W. H., McArdle J. J. Imipramine's selective suppression of an L-type calcium channel in neurons of murine dorsal root ganglia involves G proteins. J Pharmacol Exp Ther. 1992 Oct;263(1):49–53. [PubMed] [Google Scholar]
  3. Enyeart J. J., Biagi B. A., Mlinar B. Preferential block of T-type calcium channels by neuroleptics in neural crest-derived rat and human C cell lines. Mol Pharmacol. 1992 Aug;42(2):364–372. [PubMed] [Google Scholar]
  4. Fletcher E. J., Church J., MacDonald J. F. Haloperidol blocks voltage-activated Ca2+ channels in hippocampal neurones. Eur J Pharmacol. 1994 Apr 15;267(2):249–252. doi: 10.1016/0922-4106(94)90178-3. [DOI] [PubMed] [Google Scholar]
  5. Gietzen K., Wüthrich A., Bader H. R 24571: a new powerful inhibitor of red blood cell Ca++-transport ATPase and of calmodulin-regulated functions. Biochem Biophys Res Commun. 1981 Jul 30;101(2):418–425. doi: 10.1016/0006-291x(81)91276-6. [DOI] [PubMed] [Google Scholar]
  6. Gould R. J., Murphy K. M., Reynolds I. J., Snyder S. H. Antischizophrenic drugs of the diphenylbutylpiperidine type act as calcium channel antagonists. Proc Natl Acad Sci U S A. 1983 Aug;80(16):5122–5125. doi: 10.1073/pnas.80.16.5122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Hamill O. P., Marty A., Neher E., Sakmann B., Sigworth F. J. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch. 1981 Aug;391(2):85–100. doi: 10.1007/BF00656997. [DOI] [PubMed] [Google Scholar]
  8. Hidaka H., Yamaki T., Naka M., Tanaka T., Hayashi H., Kobayashi R. Calcium-regulated modulator protein interacting agents inhibit smooth muscle calcium-stimulated protein kinase and ATPase. Mol Pharmacol. 1980 Jan;17(1):66–72. [PubMed] [Google Scholar]
  9. Hille B. G protein-coupled mechanisms and nervous signaling. Neuron. 1992 Aug;9(2):187–195. doi: 10.1016/0896-6273(92)90158-a. [DOI] [PubMed] [Google Scholar]
  10. Hille B. Modulation of ion-channel function by G-protein-coupled receptors. Trends Neurosci. 1994 Dec;17(12):531–536. doi: 10.1016/0166-2236(94)90157-0. [DOI] [PubMed] [Google Scholar]
  11. Hoshi T., Aldrich R. W. Voltage-dependent K+ currents and underlying single K+ channels in pheochromocytoma cells. J Gen Physiol. 1988 Jan;91(1):73–106. doi: 10.1085/jgp.91.1.73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Inoue K., Kenimer J. G. Muscarinic stimulation of calcium influx and norepinephrine release in PC12 cells. J Biol Chem. 1988 Jun 15;263(17):8157–8161. [PubMed] [Google Scholar]
  13. Inoue K., Watano T., Koizumi S., Nakazawa K., Burnstock G. Dual modulation by adenosine of ATP-activated channels through GTP-binding proteins in rat pheochromocytoma PC12 cells. Eur J Pharmacol. 1994 Jul 15;268(2):223–229. doi: 10.1016/0922-4106(94)90192-9. [DOI] [PubMed] [Google Scholar]
  14. Jacobs E. R., DeCoursey T. E. Mechanisms of potassium channel block in rat alveolar epithelial cells. J Pharmacol Exp Ther. 1990 Nov;255(2):459–472. [PubMed] [Google Scholar]
  15. Kase H., Iwahashi K., Nakanishi S., Matsuda Y., Yamada K., Takahashi M., Murakata C., Sato A., Kaneko M. K-252 compounds, novel and potent inhibitors of protein kinase C and cyclic nucleotide-dependent protein kinases. Biochem Biophys Res Commun. 1987 Jan 30;142(2):436–440. doi: 10.1016/0006-291x(87)90293-2. [DOI] [PubMed] [Google Scholar]
  16. Klöckner U., Isenberg G. Calmodulin antagonists depress calcium and potassium currents in ventricular and vascular myocytes. Am J Physiol. 1987 Dec;253(6 Pt 2):H1601–H1611. doi: 10.1152/ajpheart.1987.253.6.H1601. [DOI] [PubMed] [Google Scholar]
  17. Koizumi S., Ikeda M., Nakazawa K., Inoue K., Nagamatsu K., Hasegawa A., Inoue K. Accentuation by pertussis toxin of the 5-hydroxytryptamine-induced potentiation of ATP-evoked responses in rat pheochromocytoma cells. Neurosci Lett. 1995 Jan 2;183(1-2):104–107. doi: 10.1016/0304-3940(94)11125-3. [DOI] [PubMed] [Google Scholar]
  18. Koizumi S., Watano T., Nakazawa K., Inoue K. Potentiation by adenosine of ATP-evoked dopamine release via a pertussis toxin-sensitive mechanism in rat phaeochromocytoma PC12 cells. Br J Pharmacol. 1994 Jul;112(3):992–997. doi: 10.1111/j.1476-5381.1994.tb13179.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kurachi Y., Nakajima T., Sugimoto T. On the mechanism of activation of muscarinic K+ channels by adenosine in isolated atrial cells: involvement of GTP-binding proteins. Pflugers Arch. 1986 Sep;407(3):264–274. doi: 10.1007/BF00585301. [DOI] [PubMed] [Google Scholar]
  20. Levin R. M., Weiss B. Selective binding of antipsychotics and other psychoactive agents to the calcium-dependent activator of cyclic nucleotide phosphodiesterase. J Pharmacol Exp Ther. 1979 Mar;208(3):454–459. [PubMed] [Google Scholar]
  21. Nakazawa K., Fujimori K., Takanaka A., Inoue K. Existence of muscarinic suppression of a K current in PC-12 pheochromocytoma cells. Am J Physiol. 1989 Nov;257(5 Pt 1):C1030–C1033. doi: 10.1152/ajpcell.1989.257.5.C1030. [DOI] [PubMed] [Google Scholar]
  22. Nakazawa K., Inoue K., Inoue K. ATP reduces voltage-activated K+ current in cultured rat hippocampal neurons. Pflugers Arch. 1994 Nov;429(1):143–145. doi: 10.1007/BF02584042. [DOI] [PubMed] [Google Scholar]
  23. Nakazawa K., Inoue K., Ohara-Imaizumi M., Fujimori K., Takanaka A. Inhibition of Ca-channels by diazepam compared with that by nicardipine in pheochromocytoma PC12 cells. Brain Res. 1991 Jul 5;553(1):44–50. doi: 10.1016/0006-8993(91)90228-n. [DOI] [PubMed] [Google Scholar]
  24. Nakazawa K., Watano T., Inoue K. Mechanisms underlying facilitation by dopamine of ATP-activated currents in rat pheochromocytoma cells. Pflugers Arch. 1993 Feb;422(5):458–464. doi: 10.1007/BF00375072. [DOI] [PubMed] [Google Scholar]
  25. Ogata N., Yoshii M., Narahashi T. Psychotropic drugs block voltage-gated ion channels in neuroblastoma cells. Brain Res. 1989 Jan 2;476(1):140–144. doi: 10.1016/0006-8993(89)91546-1. [DOI] [PubMed] [Google Scholar]
  26. Plummer M. R., Logothetis D. E., Hess P. Elementary properties and pharmacological sensitivities of calcium channels in mammalian peripheral neurons. Neuron. 1989 May;2(5):1453–1463. doi: 10.1016/0896-6273(89)90191-8. [DOI] [PubMed] [Google Scholar]
  27. Sah D. W., Bean B. P. Inhibition of P-type and N-type calcium channels by dopamine receptor antagonists. Mol Pharmacol. 1994 Jan;45(1):84–92. [PubMed] [Google Scholar]
  28. Seeman P. Brain dopamine receptors. Pharmacol Rev. 1980 Sep;32(3):229–313. [PubMed] [Google Scholar]
  29. Wooltorton J. R., Mathie A. Block of potassium currents in rat isolated sympathetic neurones by tricyclic antidepressants and structurally related compounds. Br J Pharmacol. 1993 Nov;110(3):1126–1132. doi: 10.1111/j.1476-5381.1993.tb13931.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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