Role of potassium channels in lymphocyte function and disease
2002 Athalie Clarke Award; Excellence in Research, UCI
1999 Silver Beaker Award, UCI
2001 Kaiser Permanente Award, Best Teacher in the Basic Sciences, UCI
2004 Excellence in Teaching Award, Physiology, UCI
2005 Silver Beaker Award, UCI
2005 Kaiser Permanente Award, Best Teacher in the Basic Sciences, UCI
2005 Excellence in Teaching Award, Physiology, UCI
2006 Kaiser Permanente Award, Best Teacher in the Basic Sciences, UCI
2007 Excellence in Teaching Award, Physiology, UCI
2008 Excellence in Teaching Award, Physiology, UCI
2009 Excellence in Teaching Award, Physiology, UCI
2010 Kaiser Permanente Award, Best Teacher in the Basic Sciences,UCI
2010 Excellence in Teaching Award, Physiology, UCI
We are interested in potassium channels as therapeutic targets. We identified the pivotal role of potassium channels (Kv1.3 and KCa3.1) in the immune response. We have developed specific blockers of these channels. Selective Kv1.3 blockers treat disease in rodent models of multiple sclerosis, rheumatoid arthritis, type-1 diabetes mellitus, psoriasis, autoimmune glomerulonephritis, and contact dermatitis, and they have been shown to be safe in rats and monkeys. ShK-186, a peptide inhibitor of Kv1.3, is scheduled to begin human trials in 2011. Selective KCa3.1 blockers have been shown to prevent vascular stenosis following angioplasty in rats and atherosclerosis in mice. We also developed a transgenic model for cerebellar ataxia based on targeting the KCa2.x potassium channel in deep cerebellar neurons. The results from this study suggested the possibility of using KCa2.x channel-openers as therapy for cerebellar ataxia. Based on this work a clinical trial of riluzole in cerebellar ataxia was performed in Italy and the drug was found to be effective in reducing the symptoms of the disease.
DeCoursey T.E., Chandy K.G., Gupta, S. Cahalan, M. (1984) Voltage gated potassium channels in human T lymphocytes: a role in mitogenesis? Nature 307, 465.
Chandy K.G., DeCoursey T.E., Cahalan M.D., McLaughlin C., Gupta S. (1984) Voltage-gated potassium channels are required for human T cell activation. J. Exp. Med. 160, 369.
Chandy K.G., DeCoursey T.E., Fischbach M., Talal, N., Cahalan M.D., Gupta S. (1986) Altered K+ channel expression in abnormal T lymphocytes from mice with the lpr gene mutation. Science 233, 1197.
Chandy, K. G., Williams, C., Spencer, R. H., Aguilar, B. A., Ghanshani, S., Tempel, B., Gutman, G. A. (1990) A family of three mouse K+ channel genes with intronless coding regions. Science 247, 973.
Grissmer, S., Dethlefs, B., Wasmuth, J., Gutman, G., Goldin, A. L., Cahalan, M. D., Chandy, K. G. (1990) Expression and chromosomal localization of a lymphocyte K+ channel. Proc. Natl. Acad. Sci. USA 87, 9411
Aiyar, J., Withka, J., Rizzi, J., Dethlefs, B., Simon, M., Chao-lin Lee, Boyd, J., Hall, J., Gutman, G.A., Chandy K. G. (1995). Topological map of the external vestibule at the external entrance to the pore. Neuron 15, 1169.
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. J. Biol. Chem. 271, 31013.
Chandy, K.G., Fantino, E., Wittekindt, O., Kalman, K., Tong, L.,Thanh-Hien Ho, Gutman, G. A., Crocq, M-A, Ganguli, R., Nimgaonkar, V., Morris-Rosendahl, D. J., Gargus, J.J. (1998) Isolation of a potassium channel gene, hSKCa3, containing polymorphic CAG repeat: A candidate gene for schizophrenia and bipolar disorder? Molecular Psychiatry 3, 32.
K Kalman, M. Pennington, M. D. Lanigan, A. Nguyen, Kem, R., Grissmer, S., K. Paschetto, S. Stetz, G. A. Gutman,, E. Christian+, M. D. Cahalan, R. S. Norton, Chandy, K. G. (1998) ShK-Dap22: A potent Kv1.3-specific immunosuppressive peptide. J. Biol. Chem. 273:32697-707.
Fanger, C. S. Ghanshani, N. J. Logsdon,H. Rauer, K. Kalman, J. Zhou, K. Beckingham, Chandy, KG, Cahalan, MD, Aiyar, J. (1999) Calmodulin mediates Calcium-Dependent Activation of the Intermediate Conductance KCa Channel, IKCa1. J. Biol. Chem 274:5746-5754
Rauer H, Pennington M, Cahalan M, Chandy KG (1999) Structural conservation of the pores of calcium-activated and voltage-gated potassium channels determined by a sea anemone toxin. J. Biol. Chem. 274, 21885.
Wulff, H., Miller, M., Grissmer, S., Hansel, W., Cahalan, M.D., Chandy, KG. (2000) Design of a selective inhibitor of the intermediate-conductance calcium-activated K+ channel, IKCa1: a potential immunosuppressant. Proc. Natl. Acad. Sci. USA. 97:8151-6
Ghanshani, S., Wulff, H., Neben, A., Miller, M Gutman, G.A., Cahalan, M.D., Chandy, KG. (2000) Up-regulation of the IKCa1 potassium channel during human T-cell activation: molecular mechanisms and functional consequences. J. Biol. Chem. 275, 37137
Rauer H, Lanigan MD, Pennington MW, Aiyar J, Ghanshani S, Cahalan MD, Norton RS, Chandy KG (2000) Structure-guided transformation of charybdotoxin yields an analog that selectively targets Ca2+-activated over voltage-gated K+ channels. J. Biol. Chem. 275, 1201.
Beeton, C., Wulff, H., Barbaria, J., Clot-Faybesse, O., Pennington, M., Bernard, D., Cahalan, M.D., Chandy, KG. and Béraud, E. Selective blockade of T lymphocyte K+ channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. (2001) Proc. Natl. Acad. Sci. USA. 98: 13942-13947
Ayabe, T., Wulff, H., Darmoul, D., Cahalan, M. D., Chandy, K. G, and Ouellette, A. J. (2001) Modulation of mouse Paneth cell alpha-defensin secretion by mIKCa1, a Ca2+-activated, intermediate-conductance potassium channel. J. Biol. Chem. 277, 3793.
Wulff, H., Gutman, G. A., Cahalan, M. D., Chandy, KG. (2001) Delineation of the clotrimazole/TRAM-34 binding site on the intermediate-conductance calcium-activated K+ channel, IKCa1. J. Biol. Chem. 276:32040-32045.
Shakkottai VG, Regaya I, Wulff H, Fajloun Z, Tomita H, Fathallah M, Cahalan M, Gargus JJ, Sabatier JM, Chandy KG. (2001) Design and characterization of a highly selective peptide inhibitor of the small conductance calcium-activated K+ channel, SKCa2. J. Biol. Chem. 276, 43145.
Chandy, K. G, Wulff, H., Beeton, C., Pennington, M., Gutman, G. A., Cahalan, M. D. (2004). Potassium channels as targets for specific immunomodulation. Trends in Pharmacological Sciences 25, 280-289
Kohler R, Wulff H, Eichler I, Kneifel M, Neumann D, Knorr A, Grgic I, Kampfe D, Si H, Wibawa J, Real R, Borner K, Brakemeier S, Orzechowski HD, Reusch HP, Paul M, Chandy KG, Hoyer J. (2003) Blockade of the intermediate-conductance calcium-activated potassium channel as a new therapeutic strategy for restenosis. Circulation 108, 1119-25
Wulff, H., Calabresi, P., Beeton, C., Yun, S., Allie, R., Pennington, M., Chandy, K.G. (2003). The voltage-gated Kv1.3 K+ channel in effector memory T cells as new target for MS. J. Clinical Investigation. 111, 1703-1713
Beeton, C., Wulff, H., Singh, S., Botsko, S., Crossley, G., Gutman, GA, Cahalan, MD, Pennington, M., Chandy, KG. (2003) A novel fluorescent toxin to detect and investigate Kv1.3-channel up-regulation in chronically activated T lymphocytes. J. Biol. Chem. 278, 9928.
Shakkottai, V.G, Chou, C-h, Oddo, S, Sailer, C.A., Knaus, H-G, Gutman, G.A., Barish, M.E, LaFerla, F.M., Chandy, K.G. (2004). Enhanced neuronal excitability in the absence of neurodegeneration induces cerebellar ataxia. J. Clinical Investigation 113, 582-590. (also see “Commentary” in same issue of J. Clin. Invest, and the “Highlight” in Nature Reviews Neuroscience).
Wulff, H., Knaus, H-G, Pennington, M., Chandy, K. G. (2004). K+ channel expression during B-cell differentiation: implications for immunomodulation and autoimmune disorders. J. Immunol. 173:776-786.
Villalobos C, Shakkottai VG, Chandy KG, Michelhaugh, S. K., Andrade R. (2004) SKCa channels mediate the medium but not the slow calcium-activated afterhyperpolarization in cortical neurons. J. Neuroscience 24, 3537.
Beeton, C., Pennington, M. W., Singh, S., Nugent, D., Crossley, G., Khaytin, I., Calabresi, P. A., Chandy, K. G. (2005). Targeting effector memory T cells with a selective peptide inhibitor of Kv1.3 channels for therapy of autoimmune diseases. Molecular Pharmacology 67:1369-1381.
Vennekamp, J., Wulff, H., Beeton, C., Calabresi, P. A., Grissmer, S., Hansel, W., Chandy, K. G. (2004) Kv1.3 Blocking 5-Phenylalkoxypsoralens: A new Class of Immunomodulators Molecular Pharmacology 65, 1364.
Rus, H, Pardo CA, Hu L, Darrah E, Cudrici C, Niculescu T, Niculescu F, Mullen KM,, Allie R, Guo L, Wulff H, Beeton C, Judge SIV, Kerr DA, Knaus H-G, Chandy KG, and Calabresi PA (2005). The Voltage-Gated Potassium Channel Kv1.3 is Highly Expressed on Inflammatory Infiltrates in Multiple Sclerosis Brain. Proc. Natl. Acad. Sci. USA 102: 11094-11099
Gutman GA, Chandy KG, et al. International Union of Pharmacology. XLI. (2003) Compendium of Voltage-Gated Ion Channels: Potassium Channels. Pharmacol Rev. 55, 58
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Beeton C, et al. (2008). The D-diastereomer of ShK toxin selectively blocks voltage-gated K+ channels and inhibits T lymphocyte proliferation. J. Biol. Chem. 283,988-997
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Pennington M. W., et al. (2009) Engineering a stable and selective peptide blocker of the Kv1.3 channel in T lymphocytes. Molecular Pharmacology 75:762-773.
Cahalan MD, Chandy KG. (2009). The functional network of ion channels in T lymphocytes. Immunological Reviews 231:59-87. Faculty of 1000 review by Dr. Markus Hoth
Rangaraju S, et al. (2010) Potassium channel modulation by a toxin domain in matrix metalloprotease 23. J Biol. Chem 285:9124-36.
Structural Biology and Molecular Biophysics