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The Korea Academia-Industrial cooperation Society (한국산학기술학회)
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The effect of antipsychotics and antidepressants on the TREK2 channel

TREK2 채널에 대한 항정신성약물 및 항우울제의 효과

  • Kwak, Ji-Yeon (Dept. of Physiology, College of Medicine, Inha University) ;
  • Kim, Yang-Mi (Dept. of Physiology, College of Medicine, Chungbuk National University)
  • 곽지연 (인하대학교 의과대학 생리학교실) ;
  • 김양미 (충북대학교 의과대학 생리학교실)
  • Received : 2012.04.10
  • Accepted : 2012.05.10
  • Published : 2012.05.31
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Abstract

Fluoxetine and tianeptine are commonly used as antidepressants (AD), and haloperidol and risperidone are widely used as antipsychotic drugs (APD), and it modulates various ion channels. TREK2 channel subfamily is very similar to physiological properties of TREK1 channel which can play important roles in the pathophysiology of mental disorders such as depression and schizophrenia, therefore, the pharmacological effect of psychiatric and depression drug on TREK2 channel may be similar to those of TREK1. Using the excised inside-out patch-clamp technique, we have examined the effects of APD and AD on cloned TREK2 channel expressed CHO cells. Fluoxetine (selective serotonin release inhibitor, SSRI) inhibited the TREK2 channel in a concentration-dependent manner ($IC_{50}$ $13{\mu}M$), whereas selective serotonin reuptake enhancer (SSRE) tianeptine increased without reducing the TREK2 channel activity. Haloperidol also inhibited the TREK2 channel in a concentration-dependent manner ($IC_{50}$ $44{\mu}M$), whereas even higher concentration ($100{\mu}M$) of risperidone did not completely inhibit on the activity. This study showed that TREK2 channel was preferentially blocked by fluoxetine rather than tianeptine, and inhibited by haloperidol rather than risperidone, suggesting differential effect of TREK2 channels by APD and AD may contribute to some mechanism of adverse side effects.

Fluoxetine과 tianeptine은 보편적으로 사용되는 항우울제 (AD)이며, haloperidol과 risperidone도 많이 사용되는 항정신성 (APD) 약물로 다양한 이온채널을 조절한다. TREK2 채널은 우울증과 정신분열증 같은 정신질환에 대한 병태생리학적으로 중요한 역할을 하는 TREK1 채널과 생리학적 성질이 매우 비슷하여, 정신성 및 우울증 약물의 TREK2 채널에 대한 효과가 TREK1과 유사하게 나타날 가능성이 있다. Excised inside-out 팻취 방법을 사용하여, 클론된 TREK2 채널이 발현된 CHO 세포에서 항정신성 약물과 항우울제의 효과를 조사했다. Fluoxetine (선택적 세로토닌 방출 억제제, SSRI)은 TREK2 채널을 농도 의존적으로 억제하였으나 ($IC_{50}=13{\mu}M$), tianeptine (선택적 세로토닌 재흡수 증가제, SSRE)은 TREK2 채널 활성을 감소시키지 않고 증가시켰다. Haloperidol은 TREK2 채널을 농도 의존적으로 억제하였으나 ($IC_{50}=44{\mu}M$), risperidone은 고농도 ($100{\mu}M$)에서도 TREK2 채널 활성을 완전히 억제 시키지 못했다. 본 연구는 tianeptine 보다 fluoxetine이 TREK2 채널을 더 잘 억제하고 risperidone 보다 haloperidol에 더 잘 억제됨을 보여 주었고, TREK2 채널에 대한 항정신성 약물과 항우울제의 차별적 작용이 약물 부작용의 어떤 기전에 기여 할 수 있음을 제시한다.

Keywords

References

  1. H. Y. Meltzer, et al., "The role of serotonin receptors in the action of atypical antipsychotic drugs". Curr Opin Pharmacol, Vol. 11, No. 1, pp.59-67, Feb. 2011. https://doi.org/10.1016/j.coph.2011.02.007
  2. J. Gerlach, "New antipsychotics: classification, efficacy, and adverse effects". Schizophr Bull, Vol. 17, No. 2, pp.289-309. 1991. https://doi.org/10.1093/schbul/17.2.289
  3. E. J. Fletcher, et al., "Haloperidol blocks voltage-activated $Ca^{2+}$ channels in hippocampal neurones". Eur J Pharmacol, Vol. 267, No. 2, pp.249-52, Apr. 1994. https://doi.org/10.1016/0922-4106(94)90178-3
  4. T. Kazic, et al., "Potassium channels and the development of new drugs". Med Pregl, Vol. 51, No. 11-12, pp.481-8, Nov-Dec. 1998.
  5. A. Mathie, et al., "Trafficking of neuronal two pore domain potassium channels". Curr Neuropharmacol, Vol. 8, No. 3, pp.276-86, Sep. 2010. https://doi.org/10.2174/157015910792246146
  6. S. Thummler, et al., "Antipsychotics inhibit TREK but not TRAAK channels". Biochem Biophys Res Commun, Vol. 354, No. 1, pp.284-9, Mar. 2007. https://doi.org/10.1016/j.bbrc.2006.12.199
  7. D. Thomas, et al., "The antidepressant drug fluoxetine is an inhibitor of human ether-a-go-go-related gene (HERG) potassium channels". J Pharmacol Exp Ther, Vol. 300, No. 2, pp.543-8, Feb. 2002. https://doi.org/10.1124/jpet.300.2.543
  8. D. Rampe, et al., "The antipsychotic agent sertindole is a high affinity antagonist of the human cardiac potassium channel HERG". J Pharmacol Exp Ther, Vol. 286, No. 2, pp.788-93, Aug. 1998.
  9. S. Y. Yeung, et al., "Inhibition of neuronal $K_V$ potassium currents by the antidepressant drug, fluoxetine". Br J Pharmacol, Vol. 128, No. 7, pp.1609-15, Dec.1999. https://doi.org/10.1038/sj.bjp.0702955
  10. T. Kobayashi, et al., "Inhibition of G protein-activated inwardly rectifying $K^+$ channels by fluoxetine (Prozac)". Br J Pharmacol, Vol. 138, No. 6, pp.1119-28, Mar.2003. https://doi.org/10.1038/sj.bjp.0705172
  11. Y. Ohno, et al., "Inhibition of astroglial $K_{ir4.1}$ channels by selective serotonin reuptake inhibitors". Brain Res, Vol. 1178, No. pp.44-51, Oct 31.2007. https://doi.org/10.1016/j.brainres.2007.08.018
  12. G. C. Terstappen, et al., "The antidepressant fluoxetine blocks the human small conductance calcium-activated potassium channels SK1, SK2 and SK3". Neurosci Lett, Vol. 346, No. 1-2, pp.85-8, Jul. 2003. https://doi.org/10.1016/S0304-3940(03)00574-3
  13. J. J. Pancrazio, et al., "Inhibition of neuronal Na+ channels by antidepressant drugs". J Pharmacol Exp Ther, Vol. 284, No. 1, pp.208-14, Jan.1998.
  14. C. Maertens, et al., "Block by fluoxetine of volume-regulated anion channels". Br J Pharmacol, Vol. 126, No. 2, pp.508-14, Jan.1999. https://doi.org/10.1038/sj.bjp.0702314
  15. A. Traboulsie, et al., "T-type calcium channels are inhibited by fluoxetine and its metabolite norfluoxetine". Mol Pharmacol, Vol. 69, No. 6, pp.1963-8, Jun.2006. https://doi.org/10.1124/mol.105.020842
  16. G. Chouinard, et al., "Clinical review of risperidone". Can J Psychiatry, Vol. 38 Suppl 3, No. pp.S89-95, Sep.1993.
  17. T. Mennini, et al., "Tianeptine, a selective enhancer of serotonin uptake in rat brain". Naunyn Schmiedebergs Arch Pharmacol, Vol. 336, No. 5, pp.478-82, Nov.1987.
  18. S. Kasper, et al., "Neurobiological and clinical effects of the antidepressant tianeptine". CNS Drugs, Vol. 22, No. 1, pp.15-26, 2008. https://doi.org/10.2165/00023210-200822010-00002
  19. E. Honore, "The neuronal background K2P channels: focus on TREK1". Nat Rev Neurosci, Vol. 8, No. 4, pp.251-61, Apr. 2007.
  20. M. Spedding, et al., "Synaptic plasticity and neuropathology: new approaches in drug discovery". Med Sci (Paris), Vol. 21, No. 1, pp.104-9, Jan. 2005. https://doi.org/10.1051/medsci/2005211104
  21. O. P. Hamill, et al., "Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches". Pflugers Arch, Vol. 391, No. 2, pp.85-100, Aug. 1981. https://doi.org/10.1007/BF00656997
  22. F. Franciolini, "Patch clamp technique and biophysical study of membrane channels". Experientia, Vol. 42, No. 6, pp.589-94, Jun. 1986. https://doi.org/10.1007/BF01955551
  23. H. Bang, et al., "TREK-2, a new member of the mechanosensitive tandem-pore $K^+$ channel family". J Biol Chem, Vol. 275, No. 23, pp.17412-9, Jun. 2000. https://doi.org/10.1074/jbc.M000445200
  24. Y. Kim, et al., "Synergistic interaction and the role of C-terminus in the activation of TRAAK $K^+$ channels by pressure, free fatty acids and alkali". Pflugers Arch, Vol. 442, No. 1, pp.64-72, Apr. 2001. https://doi.org/10.1007/s004240000496
  25. C. Heurteaux, et al., "Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype". Nat Neurosci, Vol. 9, No. 9, pp.1134-41, Sep. 2006. https://doi.org/10.1038/nn1749
  26. M. H. Kole, et al., "The antidepressant tianeptine persistently modulates glutamate receptor currents of the hippocampal CA3 commissural associational synapse in chronically stressed rats". Eur J Neurosci, Vol. 16, No. 5, pp.807-16, Sep. 2002. https://doi.org/10.1046/j.1460-9568.2002.02136.x
  27. Y. J. Kim, et al., "Modulation of tianeptine on ion currents induced by inhibitory neurotransmitters in acutely dissociated dorsal raphe neurons of Sprague-Dawley rats". Eur Neuropsychopharmacol, Vol. 12, No. 5, pp.417-25, Oct. 2002. https://doi.org/10.1016/S0924-977X(02)00054-8
  28. J. S. Choi, et al., "Mechanism of fluoxetine block of cloned voltage-activated potassium channel $K_{v1.3}$". J Pharmacol Exp Ther, Vol. 291, No. 1, pp.1-6, Oct. 1999.
  29. R. L. Martin, et al., "The utility of hERG and repolarization assays in evaluating delayed cardiac repolarization: influence of multi-channel block". J Cardiovasc Pharmacol, Vol. 43, No. 3, pp.369-79, Mar. 2004. https://doi.org/10.1097/00005344-200403000-00007
  30. S. N. Wu, et al., "Characterization of inhibition by risperidone of the inwardly rectifying $K^+$ current in pituitary $GH_3$ cells". Neuropsychopharmacology, Vol. 23, No. 6, pp.676-89, Dec. 2000. https://doi.org/10.1016/S0893-133X(00)00151-2
  31. K. Yokota, et al., "The effects of neuroleptics on the GABA-induced $Cl^-$ current in rat dorsal root ganglion neurons: differences between some neuroleptics". Br J Pharmacol, Vol. 135, No. 6, pp.1547-55, Mar. 2002. https://doi.org/10.1038/sj.bjp.0704608
  32. P. Gluais, et al., "Risperidone reduces $K^+$ currents in human atrial myocytes and prolongs repolarization in human myocardium". Eur J Pharmacol, Vol. 497, No. 2, pp.215-22, Aug. 2004. https://doi.org/10.1016/j.ejphar.2004.06.046