In living cells, electrical signals control a cornucopia of important physiological processes including neurotransmission, insulin secretion, and heartbeat. Electrophysiological signals are generated by proteins known as ion channels. Different cell types harbor distinct complements of channels, tuned to serve the particular functions of a cell. Establishing the identity of proteins underlying endogenous ionic currents in any particular cell type has been particularly challenging problem. Mammalian voltage-gated potassium channels are exemplars of protein diversity. They arise from a family of more than 40 genes encoding pore-forming subunits, many of which can co-assemble into functionally distinct heterotetramers, which then recruit a variety of modulatory subunits. There are no selective inhibitors for most of these proteins, and more advanced tools are needed to identify the channels underlying endogenous potassium currents. The Sack laboratory is developing serial strategies to molecularly identify the channels that underlie important yet unidentified ionic currents. By using engineering biologic macromolecules and implementing ligand evolution strategies, we are developing novel means to target specific potassium channel gene products. The new biochemical tools are being used to probe the physiological function of specific ion channel proteins, and modulate cellular electrical signaling.
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2015 Sack JT, Eum KS. Ion channel Inhibitors. Handbook of Ion Channels. CRC Press, eds J. Zheng & M. C. Trudeau. Ch. 14, 189-197.
2014 Tilley D, Eum KS, Fletcher-Taylor S, Austin DA, Dupre C, Patron L, Garcia R, Lam K, Yarov-Yarovoy V, Cohen BE, Sack JT. Chemoselective tarantula toxins report activation of wild-type ion channels in live cells. Proceedings of the National Academy of Sciences of the United States of America. 111: E4789–E4796.
2014 Ingólfsson HI, Thakur P, Herold KF, Maretzky T, Hall K, Zwama M, Yilmaz D, Hemmings HC, Blobel C, Koçer A, Sack JT, Andersen OS. Phytochemicals perturb membranes and promiscuously alter protein function. ACS Chemical Biology, 9:1788-98.
2014 Speca DJ, Ogata G, Mandikian D, Wiler SW, Eum K, Wenzel HJ, Doisy ET, Matt L, Campi KL, Golub MS, Nerbonne JM, Hell JW, Trainor BC, Sack JT, Schwartzkroin PA, Trimmer JS. Deletion of the Kv2.1 delayed rectifier potassium channel leads to neuronal and behavioral hyperexcitability. Genes, Brain and Behavior, 13:394-408.
2013 Sack JT, Stephanopoulos N, Austin DC, Francis MB, Trimmer JS. Antibody-guided photoablation of voltage-gated potassium currents. Journal of General Physiology, 142:315-324.
2011 Mandikian, D., O. Cerda, J.T. Sack, and J.S. Trimmer. A SUMO-Phospho tag team for wrestling with potassium channel gating. The Journal of general physiology. 137:435-439.
2010 Al-Sabi, A., O. Shamotienko, S.N. Dhochartaigh, N. Muniyappa, M. Le Berre, H. Shaban, J. Wang, J.T. Sack, and J.O. Dolly. Arrangement of Kv1 alpha subunits dictates sensitivity to tetraethylammonium. J Gen Physiol. 136:273-282.
2008 Sack, J.T., O. Shamotienko, and J.O. Dolly. How to Validate a Heteromeric Ion Channel Drug Target: Assessing Proper Expression of Concatenated Subunits. J Gen Physiol. 131:415-420.
2007 Sokolov, M.V., O. Shamotienko, S.N. Dhochartaigh, J.T. Sack, and J.O. Dolly. Concatemers of brain Kv1 channel alpha subunits that give similar K(+) currents yield pharmacologically distinguishable heteromers. Neuropharmacology. 53:272-282.
2006 Sack, J.T., and R.W. Aldrich. Binding of a gating modifier toxin induces intersubunit cooperativity early in the Shaker K channel's activation pathway. J Gen Physiol. 128:119-132.
2004 Sack, J.T., R.W. Aldrich, and W.F. Gilly. A gastropod toxin selectively slows early transitions in the Shaker K channel's activation pathway. J Gen Physiol. 123:685-696.
2003 Kelley, W.P., A.M. Wolters, J.T. Sack, R.A. Jockusch, J.C. Jurchen, E.R. Williams, J.V. Sweedler, and W.F. Gilly. Characterization of a novel gastropod toxin (6-bromo-2-mercaptotryptamine) that inhibits shaker K channel activity. J Biol Chem. 278:34934-34942.