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Open channel block of Kv1.3 by rosiglitazone and troglitazone: Kv1.3 as the pharmacological target for rosiglitazone

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Abstract

The effects of rosiglitazone and troglitazone were examined on cloned Kv1.3 channels stably expressed in Chinese hamster ovary cells using the whole-cell configuration of the patch-clamp technique. Rosiglitazone decreased the Kv1.3 currents and accelerated the decay rate of current inactivation in a concentration-dependent manner with an IC50 of 18.6 μM. These effects were reversible after washout of the drug. Troglitazone caused the block of Kv1.3 with a similar pattern but was five times more potent than rosiglitazone with an IC50 of 3.5 μM. The block of Kv1.3 by rosiglitazone and troglitazone was voltage-dependent at a membrane potential coinciding with the activation of the channels. Both drugs decreased the tail current amplitude and slowed the deactivation process of Kv1.3, resulting in a tail crossover phenomenon. These results indicate that rosiglitazone and troglitazone block the open state of Kv1.3 channels, suggesting that it is an important pharmacological target for rosiglitazone as a potent blocker of Kv1.3 channels.

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References

  • Barroso I, Gurnell M, Crowley VE, Agostini M, Schwabe JW, Soos MA, Maslen GL, Williams TD, Lewis H, Schafer AJ, Chatterjee VK, O’Rahilly S (1999) Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 402:880–883

    PubMed  CAS  Google Scholar 

  • Berger J, Bailey P, Biswas C, Cullinan CA, Doebber TW, Hayes NS, Saperstein R, Smith RG, Leibowitz MD (1996) Thiazolidinediones produce a conformational change in peroxisomal proliferator-activated receptor-gamma: binding and activation correlate with antidiabetic actions in db/db mice. Endocrinology 137:4189–4195

    Article  PubMed  CAS  Google Scholar 

  • Breum L, Bjerre U, Bak JF, Jacobsen S, Astrup A (1995) Long-term effects of fluoxetine on glycemic control in obese patients with non-insulin-dependent diabetes mellitus or glucose intolerance: influence on muscle glycogen synthase and insulin receptor kinase activity. Metabolism 44:1570–1576

    Article  PubMed  CAS  Google Scholar 

  • Chandy KG, Wulff H, Beeton C, Pennington M, Gutman GA, Cahalan MD (2004) K+ channels as targets for specific immunomodulation. Trends Pharmacol Sci 25:280–289

    Article  CAS  Google Scholar 

  • Choi JS, Hahn SJ, Rhie DJ, Yoon SH, Jo YH, Kim MS (1999) Mechanism of fluoxetine block of cloned voltage-activated potassium channel Kv1.3. J Pharmacol Exp Ther 291:1–6

    PubMed  CAS  Google Scholar 

  • Dal Ponte DB, Fogt DL, Jacob S, Henriksen EJ (1998) Interactions of captopril and verapamil on glucose tolerance and insulin action in an animal model of insulin resistance. Metabolism 47:982–987

    Article  Google Scholar 

  • Delpon E, Valenzuela C, Gay P, Franqueza L, Snyders DJ, Tamargo J (1997) Block of human cardiac Kv1.5 channels by loratadine: voltage-, time- and use-dependent block at concentrations above therapeutic levels. Cardiovasc Res 35:341–350

    Article  PubMed  CAS  Google Scholar 

  • Eto K, Ohya Y, Nakamura Y, Abe I, Fujishima M (2001) Comparative actions of insulin sensitizers on ion channels in vascular smooth muscle. Eur J Pharmacol 423:1–7

    Article  PubMed  CAS  Google Scholar 

  • Izumi T, Enomoto S, Hosiyama K, Sasahara K, Shibukawa A, Nakagawa T, Sugiyama Y (1996) Prediction of the human pharmacokinetics of troglitazone, a new and extensively metabolized antidiabetic agent, after oral administration, with an animal scale-up approach. J Pharmacol Exp Ther 277:1630–1641

    PubMed  CAS  Google Scholar 

  • Knock GA, Mishra SK, Aaronson PI (1999) Differential effects of insulin-sensitizers troglitazone and rosiglitazone on ion currents in rat vascular myocytes. Eur J Pharmacol 368:103–109

    Article  PubMed  CAS  Google Scholar 

  • Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA (1995) An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem 270:12953–12956

    Article  PubMed  CAS  Google Scholar 

  • Li Y, Wang P, Xu J, Desir GV (2006) Voltage-gated potassium channel Kv1.3 regulates GLUT4 trafficking to the plasma membrane via a Ca2+-dependent mechanism. Am J Physiol Cell Physiol 290:C345–C351

    Article  PubMed  CAS  Google Scholar 

  • MacDonald PE, Sewing S, Wang J, Joseph JW, Smukler SR, Sakellaropoulos G, Wang J, Saleh MC, Chan CB, Tsushima RG, Salapatek AM, Wheeler MB (2002) Inhibition of Kv2.1 voltage-dependent K+ channels in pancreatic beta-cells enhances glucose-dependent insulin secretion. J Biol Chem 277:44938–44945

    Article  PubMed  CAS  Google Scholar 

  • Roe MW, Worley JF 3rd, Mittal AA, Kuznetsov A, DasGupta S, Mertz RJ, Witherspoon SM 3rd, Blair N, Lancaster ME, McIntyre MS, Shehee WR, Dukes ID, Philipson LH (1996) Expression and function of pancreatic beta-cell delayed rectifier K+ channels. Role in stimulus-secretion coupling. J Biol Chem 271:32241–32246

    Article  PubMed  CAS  Google Scholar 

  • Snyders DJ, Yeola SW (1995) Determinants of antiarrhythmic drug action. Electrostatic and hydrophobic components of block of the human cardiac hKv1.5 channel. Circ Res 77:575–583

    PubMed  CAS  Google Scholar 

  • Valenzuela C, Delpon E, Franqueza L, Gay P, Perez O, Tamargo J, Snyders DJ (1996) Class III antiarrhythmic effects of zatebradine. Time-, state-, use-, and voltage-dependent block of hKv1.5 channels. Circulation 94:562–570

    PubMed  CAS  Google Scholar 

  • Wagstaff AJ, Goa KL (2002) Rosiglitazone: a review of its use in the management of type 2 diabetes mellitus. Drugs 62:1805–1837

    Article  PubMed  CAS  Google Scholar 

  • Willson TM, Cobb JE, Cowan DJ, Wiethe RW, Correa ID, Prakash SR, Beck KD, Moore LB, Kliewer SA, Lehmann JM (1996) The structure–activity relationship between peroxisome proliferator-activated receptor gamma agonism and the antihyperglycemic activity of thiazolidinediones. J Med Chem 39:665–668

    Article  PubMed  CAS  Google Scholar 

  • Xu J, Wang P, Li Y, Li G, Kaczmarek LK, Wu Y, Koni PA, Flavell RA, Desir GV (2004) The voltage-gated potassium channel Kv1.3 regulates peripheral insulin sensitivity. Proc Natl Acad Sci USA 101:3112–3117

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank Dr. Kaczmarek (Yale University School of Medicine, USA) for the Kv1.3 transfected CHO cells. This work was supported by a grant from the Medical Research Center, Korea Science and Engineering Foundation, Republic of Korea (R13-2002-005-01002-0).

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Authors and Affiliations

  1. Department of Physiology, Medical Research Center, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul, 137-701, South Korea

    Hye Sook Ahn, Sung Eun Kim, Hyun-Jong Jang, Myung-Jun Kim, Duck-Joo Rhie, Shin-Hee Yoon, Yang-Hyeok Jo, Myung-Suk Kim & Sang June Hahn

  2. Department of Pharmacology, Medical Research Center, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul, 137-701, South Korea

    Ki-Wug Sung & Seong Yun Kim

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  1. Hye Sook Ahn
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  2. Sung Eun Kim
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Correspondence to Sang June Hahn.

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Ahn, H.S., Kim, S.E., Jang, HJ. et al. Open channel block of Kv1.3 by rosiglitazone and troglitazone: Kv1.3 as the pharmacological target for rosiglitazone. Naunyn-Schmied Arch Pharmacol 374, 305–309 (2007). https://doi.org/10.1007/s00210-006-0118-6

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  • DOI: https://doi.org/10.1007/s00210-006-0118-6

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