Volume 10, Issue 1 (January & February 2019)                   BCN 2019, 10(1): 49-58 | Back to browse issues page


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1- Department of Physiology, Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
2- Department of Physiology, School of Medicine, Tarbiat Modares University, Tehran, Iran.
3- Department of Toxicology and Pharmacology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Abstract:  
Introduction: It is a long time that natural toxin research is conducted to unlock the medical potential of toxins. Although venoms-toxins cause pathophysiological conditions, they may be effective to treat several diseases. Since toxins including scorpion toxins target voltage-gated ion channels, they may have profound effects on excitable cells. Therefore, elucidating the cellular and electrophysiological impacts of toxins, particularly scorpion toxins would be helpful in future drug development opportunities.
Methods: Intracellular recording was made from F1 cells of Helix aspersa in the presence of calcium Ringer solution in which Na+ and K+ channels were blocked. Then, the modulation of channel function in the presence of extracellular application of F4 and F6 toxins and kaliotoxin (KTX; 50 nM and 1 μM) was examined by assessing the electrophysiological characteristics of calcium spikes.
Results: The two active toxin fractions, similar to KTX, a known Ca2+-activated K+ channel blocker, reduced the amplitude of AHP, enhanced the firing frequency of calcium spikes and broadened the duration of Ca2+ spikes. Therefore, it might be inferred that these two new fractions induce neuronal hyperexcitability possibly, in part, by blocking calcium-activated potassium channel current. However, this supposition requires further investigation using voltage clamping technique.
Conclusion: These toxin fractions may act as blocker of calcium-activated potassium channels.
Type of Study: Original | Subject: Behavioral Neuroscience
Received: 2017/10/26 | Accepted: 2018/04/30 | Published: 2019/01/1

References
1. Aboutorabi, A., Naderi, N., Gholamipourbadie, H., Zolfagharian, H., & Vatanpour, H. (2016). Voltage-gated sodium channels modulation by bothutous schach scorpion venom. Iranian Journal of Pharmaceutical Sciences, 12(3), 55-64. [DOI: 10.22034/ijps.2016.23841]
2. Aiyar, J., Rizzi, J. P., Gutman, G. A., & Chandy, K. G. (1996). The signature sequence of voltage-gated potassium channels projects into the external vestibule. Journal of Biological Chemistry, 271(49), 31013-6. [DOI:10.1074/jbc.271.49.31013] [PMID] [DOI:10.1074/jbc.271.49.31013]
3. Akanda, N., Molnar, P., Stancescu, M., & Hickman, J. J. (2009). Analysis of toxin induced changes in action potential shape for drug development. Journal Biomolecular Screening, 14(10), 1228-35. [DOI:10.1177/1087057109348378] [PMID] [PMCID] [DOI:10.1177/1087057109348378]
4. Bal, R., Janahmadi, M., Green, G. G. R., & Sanders, D. J. (2000). Effect of calcium and calcium channel blockers on transient outward current of F76 and D1 neuronal soma membranes in the subesophageal ganglia of helix aspersa. Journal of Membrane Biology, 173(3), 179-85. [DOI:10.1007/s002320001018] [PMID] [DOI:10.1007/s002320001018]
5. Bal, R., Janahmadi, M., Green, G. G. R., & Sanders, D. J. (2001). Two kinds of transient outward currents, IA and IAdepol, in F76 and D1 soma membranes of the subesophageal ganglia of Helix aspersa. Journal of Membrane Biology, 179(1), 71–8. [DOI:10.1007/s002320010038] [PMID] [DOI:10.1007/s002320010038]
6. Batista, C. V., Gómez Lagunas, F., Rodríguez de la Vega, R. C., Hajdu, P., Panyi, G., Gáspár, R., et al. (2002). Two novel toxins from the Amazonian scorpion Tityus cambridgei that block Kv1.3 and Shaker B K(+)-channels with distinctly different affinities. Biochimica Biophysica Acta, 1601(2), 123-31. [DOI:10.1016/S1570-9639(02)00458-2] [DOI:10.1016/S1570-9639(02)00458-2]
7. Battonyai, I., Krajcs, N., Serfőző, Z., Kiss, T., & Elekes, K. (2014). Potassium channels in the central nervous system of the snail, Helix pomatia: Localization and functional characterization. Neuroscience, 268, 87-101. [DOI:10.1016/j.neuroscience.2014.03.006] [DOI:10.1016/j.neuroscience.2014.03.006]
8. Bean, B. P. (2007). The action potential in mammalian central neurons. Nature Review Neuroscience, 8(6), 451-65. [DOI:10.1038/nrn2148] [PMID] [DOI:10.1038/nrn2148]
9. Beeton, C., Barbaria, J., Giraud, P., Devaux J, Benoliel A. M., Gola M., et al. (2001). Selective blocking of voltage-gated K+ channels improves experimental autoimmune encephalomyelitis and inhibits T cell activation. Journal of Immunology, 166(2), 936-44. [DOI:10.4049/jimmunol.166.2.936] [DOI:10.4049/jimmunol.166.2.936]
10. Biswas, A., Gomes, A., Sengupta, J., Datta, P., Singha S, Dasgupta, A. K., et al. (2012). Nanoparticle-conjugated animal venom-toxins and their possible therapeutic potential. Journal Venom Research, 3, 15-21. [PMID] [PMCID] [PMID]
11. Bittner, S., & Meuth, S. G. (2013). Targeting ion channels for the treatment of autoimmune neuroinflammation. Therapeutic Advances in Neurological Disorders, 6(5), 322-36. [DOI:10.1177/1756285613487782] [DOI:10.1177/1756285613487782]
12. Catterall, W. A., Cestèle, S., Yarov-Yarovoy, V., Yu, F. H., Konoki, K., & Scheuer, T. (2007). Voltage-gated ion channels and gating modifier toxins. Toxicon, 49(2), 124-41. [DOI:10.1016/j.toxicon.2006.09.022] [DOI:10.1016/j.toxicon.2006.09.022]
13. Crest, M., Jacquet, G., Gola, M., Zerrouk, H., Benslimane, A., Rochat, H. et al. (1992). Kaliotoxin, a novel peptidyl inhibitor of neuronal BK-type Ca2+-activated K+ channels characterized from Androctonus mauretanicus mauretanicus venom. Journal of Biological Chemistry, 267(3), 1640-7. [PMID] [PMID]
14. Crest, M., & Gola, M. (1993). Large conductance Ca(2+)-activated K+ channels are involved in both spike shaping and firing regulation in Helix neurones. Journal of Physiology, 465(1),265-87. [DOI:10.1113/jphysiol.1993.sp019676] [PMID] [DOI:10.1113/jphysiol.1993.sp019676]
15. Devaux, J. (2010). The C-terminal domain of ßIV-spectrin is crucial for KCNQ2 aggregation and excitability at nodes of Ranvier. Journal of Physiology, 588(Pt 23), 4719-30. [DOI:10.1113/jphysiol.2010.196022] [DOI:10.1113/jphysiol.2010.196022]
16. Duménieu, M., Fourcaud-Trocmé, N., Garcia, S., & Kuczewski, N. (2015). After Hyperpolarization (AHP) regulates the frequency and timing of action potentials in the mitral cells of the olfactory bulb: Role of olfactory experience. Physiology Reports, 3(5), pii: e12344. [DOI:10.14814/phy2.12344] [DOI:10.14814/phy2.12344]
17. Faber, E. S., & Sah, P. (2003). Ca2+-activated K+ (BK) channel inactivation contributes to spike broadening during repetitive firing in the rat lateral amygdala. Journal of Physiology, 552(Pt 2), 483-97. [DOI:10.1113/jphysiol.2003.050120] [PMID] [PMCID] [DOI:10.1113/jphysiol.2003.050120]
18. Ehling, P., Bittner, S., Budde, T., Wiendl, H., & Meuth, S.G. (2011). Ion channels in autoimmune neurodegeneration. FEBS Letter, 585(23), 3836-42. [DOI:10.1016/j.febslet.2011.03.065] [DOI:10.1016/j.febslet.2011.03.065]
19. Gola, M., Ducreux, C., & Chagneux, H. (1990). Ca2+ activated K+ current involment in neuronal function reveald by in situe single channel analysis in Helix neurones. Journal of Physiology, 420, 73-109. [DOI:10.1113/jphysiol.1990.sp017902] [PMID] [PMCID] [DOI:10.1113/jphysiol.1990.sp017902]
20. Haghdoost-Yazdi, H., Janahmadi, M., & Behzadi, G. (2008). Iberiotoxin-sensitive large conductance Ca2+ -dependent K+ (BK) channels regulate the spike configuration in the burst firing of cerebellar Purkinje neurons. Brain Research, 1212, 1-8. [DOI:10.1016/j.brainres.2008.03.030] [DOI:10.1016/j.brainres.2008.03.030]
21. Han, S., Hu, Y., Zhang, R., Yi, H., Wei, J., Wu, Y., et al. (2011). ImKTx88, a novel selective Kv1.3 channel blocker derived from the scorpion Isometrus maculates. Toxicon, 57(2), 348-55. [DOI:10.1016/j.toxicon.2010.12.015] [DOI:10.1016/j.toxicon.2010.12.015]
22. He, Y., Zou, X., Li, X., Chen, J., Jin, L., Zhang, F., et al. (2017). Activation of sodium channels by α-scorpion toxin, BmK NT1, produced neurotoxicity in cerebellar granule cells: An association with intracellular Ca2+ overloading. Archive Toxicology, 91(2), 935-948. [DOI:10.1007/s00204-016-1755-2] [DOI:10.1007/s00204-016-1755-2]
23. Hermann, A., & Erxleben, C. (1987). Charybdotoxin selectively blocks small Ca-activated K channels in Aplysia neurons. Journal of General Physiology, 90(1), 27-47. [DOI:10.1085/jgp.90.1.27] [PMID] [DOI:10.1085/jgp.90.1.27]
24. Humphries, E. S., & Dart, C. (2015). Neuronal and cardiovascular potassium channels as therapeutic drug targets: Promise and pitfalls. Journal of Biomolecular Screening, 20(9), 1055-73. [DOI:10.1177/1087057115601677] [DOI:10.1177/1087057115601677]
25. Hwang, D. S., Kim, S. K., & Bae, H. (2015). Therapeutic effects of bee venom on immunological and neurological diseases. Toxins, 7(7), 2413-21. [DOI:10.3390/toxins7072413] [DOI:10.3390/toxins7072413]
26. Ishii, T. M., Silvia, C., Hirschberg, B., Bond, C. T., Adelman, J. P., & Maylie, J. (1997). A human intermediate conductance calcium-activated potassium channel. Proceedings of the National Academy of Sciences of the United States of America, 94(21), 11651-6. [DOI:10.1073/pnas.94.21.11651] [DOI:10.1073/pnas.94.21.11651]
27. Janahmadi, M., Farajnia, S., Vatanparast, J., Abbasipour, H., & Kamalinejad, M. (2008). The fruit essential oil of Pimpinella anisum L. (Umblliferae) induces neuronal hyperexcitability in snail partly through attenuation of after-hyperpolarization. Journal of Ethnopharmacology, 120(3), 360-5. [DOI:10.1016/j.jep.2008.09.008] [DOI:10.1016/j.jep.2008.09.008]
28. Juhng, K. N., Kokate, T. G., Yamaguchi, S., Kim, B. Y., Rogowski, R. S., Blaustein, M. P., et al. (1999). Induction of seizures by the potent K+ channel-blocking scorpion venom peptide toxins tityustoxin-K (alpha) and pandinustoxin-K(alpha). Epilepsy Research, 34(2-3), 177–86. [DOI:10.1016/S0920-1211(98)00111-9] [DOI:10.1016/S0920-1211(98)00111-9]
29. Kourrich, S., Mourre, C., & Soumireu Mourat, B. (2001). Kaliotoxin, a Kv1.1 and Kv1.3 channel blocker, improves associative learning in rats. Behavioral Brain Research, 120(1), 35-46. [DOI:10.1016/S0166-4328(00)00356-9] [DOI:10.1016/S0166-4328(00)00356-9]
30. Lancaster, B., & Adams, P. R. (1986). Calcium-dependent current generating the after hyperpolarization of hippocampal-neurons. Journal of Neurophysiology, 55(6), 1268–82. [DOI:10.1152/jn.1986.55.6.1268] [PMID] [DOI:10.1152/jn.1986.55.6.1268]
31. Lange, C., Paris, C., & Celerier, M. L. (1992). The components of the venom of a spider Scodra griseipes. 1. Analysis of low molecular weight products using gas chromatography/mass spectrometry. Rapid Communication Mass Spectrometry, 6(4), 289-92. [DOI:10.1002/rcm.1290060413] [DOI:10.1002/rcm.1290060413]
32. Lee, U. S., & Cui, J. (2010). BK channel activation: Structural and functional insights. Trends in Neuroscience, 33(9), 415-23. [DOI:10.1016/j.tins.2010.06.004] [DOI:10.1016/j.tins.2010.06.004]
33. Lin, M., Hatcher, J. T., Chen, Q. H., Wurster, R. D., & Cheng, Z. J. (2010). Small conductance Ca2+-activated K+ channels regulate firing properties and excitability in parasympathetic cardiac motoneurons in the nucleus ambiguus. American Journal of Physiology Cell Physiology, 299(6), C1285-98. [DOI:10.1152/ajpcell.00134.2010] [DOI:10.1152/ajpcell.00134.2010]
34. Liu, C. Y., Lu, Z. Y., Li, N., Yu, L. H., Zhao, Y. F., & Ma, B. (2015). The role of large-conductance, calcium-activated potassium channels in a rat model of trigeminal neuropathic pain. Cephalalgia, 35(1), 16-35. [DOI:10.1177/0333102414534083] [DOI:10.1177/0333102414534083]
35. Ma, M., & Koester, J. (1996). The role of K+ currents in frequency-dependent spike broadening in Aplysia R20 neurons: A dynamic-clamp analysis. Journal of Neuroscience, 16(13), 4089-101. [DOI:10.1523/JNEUROSCI.16-13-04089.1996] [PMID] [DOI:10.1523/JNEUROSCI.16-13-04089.1996]
36. MacDonald, S. H., Ruth, P., Knaus, H. G., & Shipston, M. J. (2006). Increased large conductance calcium-activated potassium (BK) channel expression accompanied by STREX variant down regulation in the developing mouse CNS. BMC Developmental Biology, 6, 37. [DOI:10.1186/1471-213X-6-37] [DOI:10.1186/1471-213X-6-37]
37. Martin, S., Lazzarini, M., Dullin, C., Balakrishnan, S., Gomes, F.V., Ninkovic, M., et al. (2017). SK3 Channel Overexpression in Mice Causes Hippocampal Shrinkage Associated with Cognitive Impairments. Molecular Neurobiology, 54(2), 1078-1091. [DOI:10.1007/s12035-015-9680-6] [DOI:10.1007/s12035-015-9680-6]
38. Martin-Eauclaire, M. F., & Bougis, P. E. (2012). Potassium channels blockers from the venom of androctonus mauretanicus mauretanicus. Journal of Toxicology, 2012, 103608. [DOI:10.1155/2012/103608] [DOI:10.1155/2012/103608]
39. Mohan, D. K., Molnar, P., & Hickman, J. J. (2006).Toxin detection based on action potential shape analysis using a realistic mathematical model of differentiated NG108-15 cells. Biosens Bioelectron, 21(9), 1804-11. [DOI:10.1016/j.bios.2005.09.008] [PMID] [PMCID] [DOI:10.1016/j.bios.2005.09.008]
40. Mouhat, S., Jouirou, B., Mosbah, A., De Waard, M., & Sabatier, J. M. (2004). Diversity of folds in animal toxins acting on ion channels. Biochemistry Journal, 378(Pt 3):717-26. [DOI:10.1042/bj20031860] [DOI:10.1042/bj20031860]
41. Mouhat, S., Andreotti, N., Jouirou, B., & Sabatier, J. M. (2008).Animal toxins acting on voltage-gated potassium channels. Current Pharmacological Design, 14(24), 2503-18. [DOI:10.2174/138161208785777441] [DOI:10.2174/138161208785777441]
42. Palacio, S., Chevaleyre, V., Brann, D. H., Murray, K. D., Piskorowski R. A., & Trimmer, J. S. (2017). Heterogeneity in Kv2 Channel Expression Shapes Action Potential Characteristics and Firing Patterns in CA1 versus CA2 Hippocampal Pyramidal Neurons. eNeuro, 4(4), pii: ENEURO.0267-17.2017. [DOI:10.1523/ENEURO.0267-17.2017] [DOI:10.1523/ENEURO.0267-17.2017]
43. Pedarzani, P., D'hoedt, D., Doorty K. B., Wadsworth, J. D., Joseph, J. S., Jeyaseelan, K., 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. Journal of Biological Chemistry, 277(48), 46101-9. [DOI:10.1074/jbc.M206465200] [DOI:10.1074/jbc.M206465200]
44. Possani, L. D., Becerril, B., Delepierre, M., & Tytgat, J. (1999). Scorpion toxin specific for Na+-channels. European Journal of Biochemistry, 264(2), 287–300. [DOI:10.1046/j.1432-1327.1999.00625.x] [PMID] [DOI:10.1046/j.1432-1327.1999.00625.x]
45. Quintero-Hernández, V., Jiménez-Vargas, J. M., Gurrola, G. B., Valdivia, H. H., & Possani, L. D. (2013). Scorpion venom components that affect ion-channels function. Toxicon, 76, 328-42. [DOI:10.1016/j.toxicon.2013.07.012] [PMID] [PMCID] [DOI:10.1016/j.toxicon.2013.07.012]
46. Sah, P., & Faber, E. S. L. (2002). Channels underlying neuronal calcium-activated potassium currents. Progress Neurobiology, 66(5), 345-53. [DOI:10.1016/S0301-0082(02)00004-7] [DOI:10.1016/S0301-0082(02)00004-7]
47. Sah, P. (1996). Ca(2+)-activated K+ currents in neurones: types, physiological roles and modulation. Trends in Neuroscience, 19(4), 150-4. [DOI:10.1016/S0166-2236(96)80026-9] [DOI:10.1016/S0166-2236(96)80026-9]
48. Sakakibara, M., Okuda, F., Nomura, K., Watanabe, K., Meng, H., & Horikoshi, T., et al. (2005). Potassium currents in isolated statocyst neurons and RPeD1 in the pond snail, Lymnaea stagnalis. Journal of Neurophysiology, 94(6), 3884-92. [DOI:10.1152/jn.01163.2004] [DOI:10.1152/jn.01163.2004]
49. Solntseva, E. I. (1995). Properties of slow early potassium current in neurons of snail Helix pomatia. General Pharmacology, 26(8), 1719-26. [DOI:10.1016/0306-3623(95)00066-6] [DOI:10.1016/0306-3623(95)00066-6]
50. Storm, J. F. (1987). Action potential repolarization and a fast after-hyperpolarization in rat hippocampal pyramidal cells. Journal of Physiology, 385,733-59. [DOI:10.1113/jphysiol.1987.sp016517] [PMID] [DOI:10.1113/jphysiol.1987.sp016517]
51. Tamaddon, H., Ghasemi, Z., Vatanpour, H., & Janahmadi, M. (2014). [The effects of two fractions isolated from buthotus schach scorpion venom on action potential properties in snail neurons (Persian)]. Research in Medicine, 38(2), 86-92.
52. Thompson, S. H. (1977). Three pharmacologically distinct potassium channels in molluscan neurones. Journal of Physiology, 265(2), 465-88. [DOI:10.1113/jphysiol.1977.sp011725] [PMID] [PMCID] [DOI:10.1113/jphysiol.1977.sp011725]
53. Valverde, P., Kawai, T., & Taubman, M. A. (2004). Selective blockade of voltage-gated potassium channels reduces inflammatory bone resorption in experimental periodontal disease. Journal of Bone and Mineral Research, 19(1), 155-64. [DOI:10.1359/jbmr.0301213] [DOI:10.1359/jbmr.0301213]
54. Vatanparast, J., Janahmadi, M., & Asgari, A. R. (2006).The functional consequences of paraoxon exposure in central neurones of land snail, Caucasotachea atrolabiata, are partly mediated through modulation of Ca2+ and Ca2+-activated K+ channels. Comparative Biochemistry Physiology Toxicology Pharmacology, 143(4), 464-72. [DOI:10.1016/j.cbpc.2006.04.008] [DOI:10.1016/j.cbpc.2006.04.008]
55. Vatanpour, H., Ahmadi, F., ZareMirakabadi, A., & Jalali, A. (2012). Two biological active fractions isolated from Buthotus Schach (BS) scorpion venom examined on striated muscle preparation, in-vitro. Iranian Journal of Pharmaceutical Research, 11(3), 905-911. [PMID] [PMCID] [PMID] [PMCID]
56. Ye , F., Hu, Y., Yu, W., Xie, Z., Hu, J., Cao, Z., et al. (2016). The scorpion toxin analogue BmKTX-D33H as a potential Kv1.3 channel-selective immunomodulator for autoimmune diseases. Toxins, 8(4), 115. [DOI:10.3390/toxins8040115] [PMID] [PMCID] [DOI:10.3390/toxins8040115]
57. Zachariae, C. O., Kaltoft, K., & Thestrup-Pedersen, K. (1992). Human T lymphocytes and T-cell lines as target cells for lymphocyte chemotaxis. Archive Dermatology Research, 284(2), 77-81. [DOI:10.1007/BF00373373] [DOI:10.1007/BF00373373]
58. Zhang, Y. (2015).Why do we study animal toxins? Dongwuxue Yanjiu, 36(4), 183–222. [PMID] [PMCID] [PMID] [PMCID]
59. Zuo, X. P., & Ji, Y. H. (2004). Molecular mechanism of scorpion neurotoxins acting on sodium channels: Insight into their diverse selectivity. Molecular Neurobiology, 30(3), 265-78. [DOI:10.1385/MN:30:3:265] [DOI:10.1385/MN:30:3:265]

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