Jon Sack, Ph.D.
4135 Tupper Hall
For more information visit the Laboratory Website.
Developing new means of imaging and controlling ion channel signaling
Ion channel proteins in our cell membranes create electrical signals. Ion channels control many physiological processes including hormone secretion, heartbeat, muscle contraction, and neurotransmission. In the Sack lab we study ion channels themselves, as this fundamental physiology research has implications for every electrically excitable cell in our body. Our focus is on creating molecular tools to image and control the physiological activity of specific voltage gated ion channels. These research tools have potential uses for study or treatment of many disease states such as cardiac arrhythmia or neuropathic pain that involve electrical signaling dysfunction.
Seeing ion channel activity
Our ion channels can open and close hundreds of times per second, but this activity has been invisible to medical imaging technologies. We have recently developed methods that, for the first time, enable imaging of ion channel activity without genetic or chemical modification of the channel's structure, and thus have potential as medical diagnostic imaging agents. Our imaging methods involve molecules that bind to ion channels only when they adopt specific conformations. When ion channels change their activity, the probes bind to or dissociate from the channels. We have labeled these probes with fluorescent reporters, so ion channel activity can be imaged by today's radically advancing fluorescence microscope technologies. Ion channel activity probes are a first step towards new medical imaging technology that could diagnose the functioning of specific ion channels in health and disease.
Controlling ion channel activity
The human body expresses hundreds of different types of ion channel proteins. Each channel type has a distinct, unique physiological function. Many physiologic events such as insulin secretion, or pain signaling are driven by a unique complement of ion channels. These processes can be up- or down-regulated by modulating their ion channels. We are developing serial strategies to selectively modulate ion channel types that control specific physiological functions. Our goal is to develop selective ion channel therapies without reduced side-effects that control electrical dysfunctions, such as neuropathic pain.
Thiffault I, Speca DJ, Austin DC, Cobb MM, Eum KS, Safina NP, Grote L, Farrow EG, Miller N, Soden S, Kingsmore SF, Trimmer JS, Saunders CJ, Sack JT. A novel epileptic encephalopathy mutation in KCNB1 disrupts Kv2.1 ion selectivity, expression, and localization. Journal of General Physiology 2015 Nov;146:399-410.
Sack JT, Tilley DC. What keeps Kv channels small? The molecular physiology of modesty. Journal of General Physiology, 2015 Aug;146:123-7.
Cobb MM, Austin DC, Sack JT, Trimmer JS. Cell Cycle-dependent Changes in Localization and Phosphorylation of the Plasma Membrane Kv2.1 K+ Channel Impact Endoplasmic Reticulum Membrane Contact Sites in COS-1 Cells. J Biol Chem 2016 Mar 11;290:29189-29201.
Chen-Izu Y, Shaw RM, Pitt GS, Yarov-Yarovoy V, Sack JT, Abriel H, Aldrich RW, Belardinelli L, Cannell MB, Catterall WA, Chazin WJ, Chiamvimonvat N, Deschenes I, Grandi E, Hund TJ, Izu LT, Maier LS, Maltsev VA, Marionneau C, Mohler PJ, Rajamani S, Rasmusson RL, Sobie EA, Clancy CE, Bers D., Na+ Channel Function, Regulation, Structure, Trafficking and Sequestration. Journal of Physiology, 2015 Mar 15;593:1347-60.
Gupta K, Zamanian M, Bae C, Milescu M, Krepkiy D, Tilley DC, Sack JT, Yarov-Yarovoy V, Kim JI, Swartz KJ. Tarantula toxins use common surfaces for interacting with Kv and ASIC ion channels. eLife, 2015 May 7;4:e06774.
Sack JT, Eum KS. Ion channel Inhibitors. Handbook of Ion Channels. CRC Press, eds J. Zheng & M. C. Trudeau. 2015 Ch. 14, 189-197.
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. 2014 Nov 4;111: E4789–E4796.
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, 2014 Aug 15;9:1788-98.
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, 2014 Apr;13:394-408.
Sack JT, Stephanopoulos N, Austin DC, Francis MB, Trimmer JS. Antibody-guided photoablation of voltage-gated potassium currents. Journal of General Physiology, 2013 Sep;142:315-324.
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. 2011 May;137:435-439.
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. 2010 Sep;136:273-282.
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. 2008 May;131:415-420.
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. 2007 Aug;53:272-282.
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. 2006 Jul;128:119-132.
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. 2004 Jun;123:685-696.
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. 2003 Sep 12;278:34934-34942.
- National Institutes of Health
- American Heart Association
- Department of Energy