Heike Wulff

Assistant Professor Ph.D., University of Kiel, Germany, 1998 Office Phone: (530) 754-6135 E-mail: hwulff@ucdavis.edu

Research Interest:
Ion channels in the immune system

Research Synopsis:
My laboratory studies the role of potassium channels in the immune system. Potassium channels are proteins that tunnel the outer membrane of cells allowing for the quick flow of potassium ions in and out of the cell. In human T and B lymphocytes the voltage-gated potassium channel Kv1.3 and the calcium-activated potassium channel IKCa1 are critically involved in regulation of membrane potential, calcium signaling and mitogen or antigen induced proliferation. Expression of these two channels changes dramatically as T and B cells differentiate from naïve into memory cells, allowing the selective targeting of memory T and B cells with Kv1.3 blocking compounds. Kv1.3 is therefore regarded as promising target for the treatment of autoimmune diseases such as multiple sclerosis and type-1 diabetes. Through a combination of synthetic medicinal chemistry and electrophysiology we have in the past designed a selective blocker for IKCa1 and are in the process of developing a small molecule Kv1.3 blocker. Another project in my lab is the study of the functional role of potassium channels in oncogenesis and the identification of possible new targets for the treatment of multiple myeloma and other lymphomas.

Wulff H., Rauer H., Düring T., Hanselmann C., Ruff K., Wrisch A., Grissmer S., Hänsel W. (1998) Alkoxypsoralens: Novel Nonpeptide Blockers of Shaker-type K+ Channels: Synthesis and Photoreactivity. J. Med. Chem. 41:4542-4549. Abstract.

Wulff H., Miller, M.J., Hänsel W., Grissmer, S., Cahalan, M.D., Chandy, K.G. (2000). Design of a potent and selective inhibitor of the intermediate-conductance Ca2+-activated K+ channel, IKCa1: A potential immunosuppressant. Proceedings of the National Academy of Sciences 97: 8151-8156.Abstract.

Ghanshani S., Wulff H., Miller M. J., Rohm H., Neben, A., Gutman G.A., Cahalan M.D., Chandy, K.G (2000). Up-regulation of the IKCa1 potassium channel during T-cell activation: Molecular mechanism and functional consequences. Journal of Biological Chemistry 275: 31137-37149. Abstract.

Wulff H., Gutman G.A., Cahalan M.D., Chandy K.G. (2001) Delineation of the clotrimazole/TRAM-34 binding site on the intermediate-conductance calcium-activated potassium channel, IKCa1. Journal of Biological Chemistry 276: 32040-32045.Abstract

Beeton C.*, Wulff H.* (*joint first authors), Barbaria J., Clot-Faybesse O., Pennington M., Bernard D., Cahalan M.D., Chandy K.G., Béraud E. (2001). Selective blockade of T lymphocyte K+ channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. Proceedings of the National Academy of Sciences USA 98: 13942-13947.Abstract

Shakkotai V.G., Regaya I., Wulff H., Fajloun Z., Tomita H., Fathallah M., Cahalan M., Gargus J.J., Sabatier J.-M., Chandy K.G. (2001). Design and characterization of a higly selective peptide inhibitor of the small conductance calcium-activated K+ channel, SKCa2. In press: Journal of Biological Chemistry 276: 43145-43151. Abstract

Cahalan M. D., Wulff H., Chandy K. G. (2001). Molecular properties and physiological roles of ion channels in the immune system. Journal of Clinical Immunology 21: 235-252. Abstract

Ayabe T., Wulff H., Darmoul D., Cahalan M.D., Chandy K.G., Ouellette A.J. (2002) Modulation of Mouse Paneth Cell a-Defensin Secretion by mIKCa1, a Ca2+-activated, Intermediate-Conductance Potassium Channel. Journal of Biological Chemistry 277: 3793-3800. Abstract

Bardien-Kruger S., Wulff H., Arieff Z., Brink P., Chandy K.G., Corfield V. (2002) Characterization of the human voltage-gated potassium channel gene, KCNA7, a candidate gene for inherited cardiac disorders, and its exclusion as cause of progressive familial heart block I (PFHBI). European Journal of Human Genetics 10:36-43. Abstract.

Beeton C., Wulff H., Singh S., Botsko S., Crossley G., Gutamn G.A., Cahalan, M.D., Pennington M., Chandy K.G. (2002) A novel fluorescent toxin to detect and investigate Kv1.3 channel up-regulation in chronically activated T lymphocytes. Journal of Biological Chemistry 278: 9928-9937. Abstract

Wulff H., Calabresi P.A., Allie R., Yun S., Pennington M., Beeton C., Chandy K.G. The voltage-gated Kv1.3 K+ channel in effector memory T cells as new target for MS. Journal of Clinical Investigation 111: 1703-1713. Abstract

Köhler R., Wulff H., Eichler I., Kneifel M., Neumann D., Knorr A., Grgic I., Brakemeier S., Orzechowski H.-D., Reusch P.H., Chandy K.G., Hoyer J. (2003) Blockade of the IKCa1 Ca2+-activated K+ channel as a new therapeutic strategy for restenosis. Circulation 108:119-1125. Abstract.

Wulff H., Beeton C., Chandy K.G. (2003) Potassium channels as therapeutic targets for autoimmune disorders. Current Opinion in Drug Discovery & Development 6:640-647. Abstract.

Gutman G.A., Chandy K.G., Adelman J.P., Aiyar J., Bayliss D.A., Clapham D.E., Covarriubias M., Desir G.V., Furuichi K., Ganetzky B., Garcia M.L., Grissmer S., Jan L.Y., Karschin A, Kim D, Kuperschmidt S, Kurachi Y, Lazdunski M, Lesage F, Lester HA, McKinnon D., Nichols C.G., O'Kelly I., Robbins J., Robertson G.A., Rudy B., Sanguinetti M., Seino S., Stuehmer W., Tamkun M.M., Vandenberg C.A., Wei A., Wulff H., Wymore R.S. (2003) International Union of Pharmacology. XLI. Compendium of Voltage-Gated Ion Channels: Potassium channels. Pharmacological Reviews 55:583-586. Abstract.

Baell J.B., Gable R.W., Harvey A.J., Toovey N., Herzog T., Hänsel W., Wulff H. (2004) Kellinone derivatives as blockers of the voltage-gated potassium channel Kv1.3: Synthesis and immunosuppressive activity. Journal of Medicinal Chemistry 47:2326-2336. Abstract.

Vennekamp J.*, Wulff H.* (*joint first authors), Beeton C., Calabresi P.A., Grissmer S., Hänsel W., Chandy K.G. (2004) Kv1.3 blocking 5-Phenylalkoxypsoralens: A new class of immunomodultors. Molecular Pharmacology. 65:1364-1374. Abstract.

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. Abstract.

Mouhat S., Mosbah A., Visan V., Wulff H., Delepierre M., Darbon H., Grissmer S., De Waard M., and Sabatier J.-M. (2004) The "functional" dyad of scorpion toxin Pi1 is not itself a prerequisite for toxin binding to the voltage-gated Kv1.2 potassium channels. Biochemical Journal 377:25-36. Abstract.

Wulff H., Knaus H. G., Pennington M., and Chandy, K. G. (2004) K+ channel expression during B-cell differentiation: implications for immunomodulation and autoimmunity. Journal of Immunology 173:776-786. Abstract.

Mouhat S., Visan V., Ananthakrishnan S., Wulff H., Grissmer S., Darbon H., De Waard M., and Sabatier J.-M. (2004) K+ channel types targeted by synthetic OSK1, a toxin from Orthochirus scrobiculosus scorpion venom. Biochemical Journal 385:35-104.  Abstract.

Beeton C, Pennington MW, Wulff H, Singh S, Nugent D, Crossley G, Khaytin I, Calabresi PA, Chen CY, Gutman GA, Chandy KG. (2005) Targeting effector memory T cells with a selective peptide inhibitor of Kv1.3 channels for therapy of autoimmune diseases. Molecular Pharmacology 67:1369-81. Abstract.

Rus, H., Pardo, C. A., Hu, L., Darrah, E., Cudrici, C., Niculescu, T., Niculescu, F., Mullen, K. M., Allie, R., Guo, L., Wulff, H., Beeton, C., Judge, S. I., Kerr, D. A., Knaus, H. G., Chandy, K., G., Calabresi, P. A. (2005) The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain.  Proc. Natl Acad Sci U S A 102:(31)11094-11099. Abstract

Schmitz, A., Sankaranarayanan, A., Azam, P., Schmidt-Lassen, K., Homerick, D., Hansel, W., Wulff, H. (2005)  Design of PAP-1, a selective small molecule Kv1.3 blocker, for the supression of effector memory T cells in autoimmune diseases. Mol Pharmacol. 68(5)1254-1270.  Abstract

Mouhat, S., Teodorescu, G., Homerick, D., Visan, V., Wulff, H., Wu, Y., Grissmer, S., Darbon, H., DeWaard, M., Sabatier, J. M. (2006)  Pharmacological profiling of Orthochirus scrobiculosus toxin 1 analogues with a trimmed N-terminal domain. Mol Pharmacol. 69:(1)354-362. Abstract

Harvey, A. J., Baell, J. B., Toovey, N., Homerick, D., Wulff, H. (2006) A new class of blockers of the voltage-gated potassium channel Kv1.3 via modification of the 4- or 7-position of khellinone. J Med Chem 49:(4)1433-1441. Abstract