Abstract
Apamin is frequently used as a specific blocker of small-conductance Ca2+-activated (SK type) K+ channels. Here we show that the small neurotoxin is not as specific as anticipated. It is also a high-affinity inhibitor with an IC50 of 13 nM of the Kv1.3 channel; it blocks the latter with potency similar to the Kv1.3 blocker PAP-1. Since SK type channels and Kv1.3 channels are frequently coexpressed in different tissues such as cells of the immune system, apamin must be used with caution as a pharmacological tool.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Alvarez-Fischer D, Noelker C, Vulinovic F et al (2013) Bee venom and its component apamin as neuroprotective agents in a Parkinson disease mouse model. PLoS One 8:e61700. doi:10.1371/journal.pone.0061700
Bartok A, Toth A, Somodi S, Szanto TG, Hajdu P, Panyi G, Varga Z (2014) Margatoxin is a non-selective inhibitor of human Kv1.3 K+ channels. Toxicon 87:6–16. doi:10.1016/j.toxicon.2014.05.002
Beeton C, Wulff H, Standifer EN et al (2006) Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases. Proc Natl Acad Sci USA 103:17414–17419. doi:10.1073/pnas.0605136103
Benton DCH, Garbarg M, Moss GWJ (2013) The relationship between functional inhibition and binding for KCa2 channel blockers. PLoS One 8:e73328. doi:10.1371/journal.pone.0073328
Cahalan MD, Chandy KG (2009) The functional network of ion channels in T lymphocytes. Immunol Rev 231:59–87. doi:10.1111/j.1600-065X.2009.00816.x
Cahalan MD, Wulff H, Chandy GK (2001) Molecular properties and physiological roles of ion channels in the immune system. J Clin Immunol 21:235–252. doi:10.1023/A:1010958907271
Castle NA, Haylett DG, Jenkinson DH (1989) Toxins in the characterization of potassium channels. Trends Neurosci 12:59–65. doi:10.1016/0166-2236(89)90137-9
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. doi:10.1016/j.tips.2004.03.010
Chang PC, Turker I, Lopshire JC, Masroor S, Nguyen BL, Tao W, Rubart M, Chen PS, Chen Z, Ai T (2013) Heterogeneous upregulation of apamin-sensitive potassium currents in failing human ventricles. J Am Heart Assoc 2:e004713. doi:10.1161/JAHA.112.004713
Ghanshani S, Wulff H, Miller MJ, Rohm H, Neben A, Gutman GA, Cahalan MD, Chandy KG (2000) Up-regulation of the IKCa1 potassium channel during T-cell activation. J Biol Chem 275:37137–37149. doi:10.1074/jbc.M003941200
Grissmer S, Lewis RS, Cahalan MD (1992) Ca2+ -activated K+ channels in human leukemic T cells. J Gen Physiol 99:63–84
Habermann E (1972) Bee and wasp venoms. Science 177:314–322 (PMID:4113805)
Hanselmann C, Grissmer S (1996) Characterization of apamin-sensitive Ca2+—activated potassium channels in human leukaemic T lymphocytes. J Physiol 496:627–637 (PMCID:PMC1160851)
Kastin AJ (2011) Apamin. Academic Press, Baton Rouge, LA, USA, Handbook of biologically active peptides, p 391
Khanna R, Roy L, Zhu X, Schlichter LC (2001) K+ channels and the microglial respiratory burst. Am J Physiol Cell Physiol 280:C796–C806 (PMID: 11245596)
Kim JY, Kim KH, Lee WR et al (2015) Apamin inhibits PDGF-BB-induced vascular smooth muscle cell proliferation and migration through suppressions of activated Akt and Erk signaling pathways. Vascul Pharmacol 70:8–14. doi:10.1016/j.vph.2014.12.004
Kuras Z, Kucher V, Gordon SM, Neumeier L, Chimote AA, Filipovich AH, Conforti L (2012) Modulation of Kv1.3 channels by protein kinase AI in T lymphocytes is mediated by the disc large l-tyrosine kinase Lck complex. Am J Physiol Cell Physiol 302:C1504–C1512. doi:10.1152/ajpcell.00263.2011
Levy DI, Deutsch C (1996) Recovery from C-type inactivation is modulated by extracellular potassium. Biophys J 70(2):798–805 (PMCID: PMC1224979)
Pedarzani P, D’hoedt D, Doorty KB et al (2002) Tamapin, a venom peptide from the indian red scorpion (Mesobuthus tamulus) that targets small conductance Ca2+-activated K+ channels and afterhyperpolarization currents in central neurons. JBC 277:46101–46109
Pereira LE, Villinger F, Wulff H, Sankaranarayanan A, Raman G, Ansari AA (2007) Pharmacokinetics, toxicity and functional studies of the selective Kv1.3 channel blocker PAP-1 in rhesus macaques. Exp Biol Med 232:1338–1354. doi:10.3181/0705-RM-148
Pérez-Verdaguer M, Capera J, Serrano-Novillo C et al (2016) The voltage-gated potassium channel Kv1.3 is a promising multitherapeutic target against human pathologies. Epert Opin Ther Targets 20:577–591. doi:10.1517/14728222.2016.1112792
Schmitz A, Sankaranarayanan A, Azam P, Schmidt-Lassen K, Homerick K, Hansel W, Wulff H (2005) Design of PAP-1, a selective small molecule Kv1.3 blocker, for the suppression of effector memory T cells in autoimmune diseases. Mol Pharmacol 68:1254–1270. doi:10.1124/mol.105.015669
van der Staay FJ, Fanelli RJ, Blokland A, Schmidt BH (1999) Behavioral effects of apamin, a selective inhibitor of the SK(Ca)-channel, in mice and rats. Neurosci Biobehav R 23(8):1087–1110 (PMID:10643819)
Weaver AK, Bomben VC, Sontheimer H (2006) Expression and function of calcium-activated potassium channels in human glioma cells. Glia 54:223–233. doi:10.1002/glia.20364
Yi F, Ling T-Y, Lu T, Wang X-L, Li J, Claycomb WC, Shen W-K, Lee H-C (2015) Down-regulation of the small conductance calcium-activated potassium channels in diabetic mouse atria. J Biol Chem 290:7016–7026. doi:10.1074/jbc.M114.607952
Acknowledgements
This work was supported in part by the BMBF (project 02NUK017A) and GRK 1657. Special thanks to the students Lisa Noll, Vanessa Kohl and David Schul.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Voos, P., Yazar, M., Lautenschläger, R. et al. The small neurotoxin apamin blocks not only small conductance Ca2+ activated K+ channels (SK type) but also the voltage dependent Kv1.3 channel. Eur Biophys J 46, 517–523 (2017). https://doi.org/10.1007/s00249-016-1196-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00249-016-1196-0