Jon Sack, Ph.D.
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.
Graduate Group Affiliations
An updated list of current publications: PubMed
Marquis MJ, Sack JT. Mechanism of use-dependent Kv2 channel inhibition by RY785. Journal of General Physiology 154:e202112981 (2022) doi: 10.1085/jgp.202112981.
Sepela RJ, Stewart RG, Valencia LA, Thapa P, Wang Z, Cohen BE, Sack JT. The AMIGO1 adhesion protein activates Kv2.1 voltage sensors. Biophysical Journal. (2022). doi: 10.1016/j.bpj.2022.03.020.
Sack JT. K+ takes the crown: Selective activation of non-selective crown ether channels. Biophysical Journal. 121:863-864 (2022) doi: 10.1016/j.bpj.2022.02.020.
Thapa P, Stewart R, Sepela RJ, Vivas O, Parajuli LK, Lillya M, Fletcher-Taylor S, Cohen BE, Zito K, Sack JT. EVAP: A two-photon imaging tool to study conformational changes in endogenous Kv2 channels in live tissues. Journal of General Physiology 153:e202012858 (2021)
Stewart R, Cohen BE, Sack JT. Fluorescent toxins as ion channel activity sensors. Methods in Enzymology 653:295-318. (2021) doi: 10.1016/bs.mie.2021.02.014.
Fletcher-Taylor S, Thapa P, Sepela RJ, Kaakati R, Yarov-Yarovoy V, Sack JT, Cohen BE. Distinguishing Potassium Channel Resting State Conformations in Live Cells with Environment-Sensitive Fluorescence. ACS Chemical Neuroscience (2020) doi:10.1021/acschemneuro.0c00276.
Tilley DC, Angueyra JM, Eum KS, Kim H, Chao LH, Peng AW, Sack JT. The tarantula toxin GxTx detains K+ channel gating charges in their resting conformation. Journal of General Physiology 151:292-315 (2019) doi:10.1085/jgp.201812213
Furutani K, Tsumoto K, Chen IS, Handa K, Yamakawa Y, Sack JT, Kurachi Y. Facilitation of IKr current by some hERG channel blockers suppresses early afterdepolarizations. Journal of General Physiology 151:214-230 (2019) doi:10.1085/jgp.201812192
Mann VR, Powers AS, Tilley DC, Sack JT, Cohen BE. Azide-Alkyne Click Conjugation on Quantum Dots by Selective Copper Coordination. ACS Nano 12, 4469-4477 (2018)
Kirmiz M, Palacio S, Thapa P, King AN, Sack JT, Trimmer JS. Remodeling neuronal ER-PM junctions is a conserved nonconducting function of Kv2 plasma membrane ion channels. Molecular Biology of the Cell 29: 2410-2432 (2018)
Dockendorff C, Gandhi DM, Kimball IH, Eum KS, Rusinova R, Ingolfsson HI, Kapoor R, Peyear T, Dodge MW, Martin SF, Aldrich RW, Andersen OS, Sack JT. Synthetic Analogues of the Snail Toxin 6-Bromo-2-mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Modulation of Voltage-Gated Potassium Channels. Biochemistry 57:2733-2743 (2018)
Sepela RJ, Sack JT. Taming unruly chloride channel inhibitors with rational design. Proceedings of the National Academy of Sciences of the United States of America 115:5311-5313 (2018)
Sack JT. The envenomation of general physiology throughout the last century. Journal of General Physiology 149:975-983 (2017)
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 146:399-410 (2015)
Sack JT, Tilley DC. What keeps Kv channels small? The molecular physiology of modesty. Journal of General Physiology 146:123-7 (2015)
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. Journal of Biological Chemistry 290:29189-29201 (2015)
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 593:1347-60 (2015)
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, 4:e06774 (2015)
Sack JT, Eum KS. Ion channel Inhibitors. Handbook of Ion Channels. CRC Press, eds J. Zheng & M. C. Trudeau. Ch. 14, 189-197 (2015)
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 (2014)
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 (2013)
Mandikian D, Cerda O, Sack JT, Trimmer JS. A SUMO-Phospho tag team for wrestling with potassium channel gating. Journal of General Physiology 137:435-439 (2011)
Al-Sabi A, Shamotienko O, Ní Dhochartaigh S, Muniyappa N, LeBerre M, Shaban H, Wang J, Sack JT, Dolly JO. Arrangement of Kv1 alpha subunits dictates sensitivity to tetraethylammonium. Journal of General Physiology 136: 273-282 (2010)
Sack JT, Shamotienko O, Dolly JO. How to validate a heteromeric ion channel drug target: Assessing Proper Expression of Concatenated Subunits. Journal of General Physiology 131:415-20 (2008)
Sokolov MV, Shamotienko O, Dhochartaigh SN, Sack JT, Dolly JO. Concatemers of brain Kv1 channel alpha subunits that give similar K(+) currents yield pharmacologically distinguishable heteromers. Neuropharmacology 53:272-82 (2007)
Sack JT, Aldrich RW. Binding of a gating modifier toxin induces intersubunit cooperativity early in the Shaker K channel's activation pathway. Journal of General Physiology 128:119-32 (2006)
Sack JT, Aldrich RW, Gilly WF. A gastropod toxin selectively slows early transitions in the Shaker K channel's activation pathway. Journal of General Physiology 123:685-96 (2004)