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Senior Investigator

Kenton J. Swartz, Ph.D.

Molecular Physiology and Biophysics Section

Porter Neuroscience Research Center
Building 35 Room 3D-973
35 Convent Drive, MSC3701
Bethesda MD 20892-3701
Office: (301) 435-5652
Lab: (301) 435-5653
Fax: (301) 435-5666

Dr. Swartz received his B.S. in Chemistry and Biology from Eastern Mennonite College in 1986. He received his Ph.D. in Neurobiology from Harvard University in 1993 where he worked with Bruce Bean studying the regulation of voltage-gated calcium channels by G-proteins and protein kinases. He did postdoctoral training with Roderick MacKinnon at Harvard Medical School, where he began isolating and studying toxins that interact with voltage-activated potassium channels. Dr. Swartz joined NINDS as an Investigator in 1997 to establish a laboratory studying the structure and operational mechanisms of ion channel proteins. He was promoted to Senior Investigator in 2003, received the NIH Directors Award for Scientific Achievement in 2008 and the Kenneth S. Cole Award from the Biophysical Society in 2017. His laboratory is currently using biochemical, molecular biological, biophysical and structural techniques to investigate the structure and functional mechanisms of voltage-activated ion channels, TRP channels and P2X receptor channels.

The research focus of the laboratory is to understand how ion channel proteins sense critical biological stimuli, including membrane voltage, temperature and chemical signals. Understanding the structure and mechanisms of voltage-activated ion channels is of fundamental importance because these proteins generate nerve impulses and thereby enable neurons to signal rapidly over long distances. A mechanistic understanding of these proteins is of medical significance because they are involved in many diseases, and are widely targeted by therapeutic drugs. X-ray structures of voltage-activated potassium (Kv) channels in activated/open states have led to new ideas about how interactions between voltage-sensing domains and the lipid membrane may be crucial for the function of these channels. We are exploring this theme using a range of approaches, including using tarantula toxins that bind to voltage-sensing domains within the membrane to investigate the protein-lipid interface and solve the structure of a resting/closed state. We have also discovered a new protein that contains an identifiable S1-S4 voltage-sensing domain and large cytoplasmic termini, which we named Coupled Voltage Sensor (CVS). Our results suggest that CVS is a functional voltage sensor, and we are currently testing the hypothesis that CVS interacts with a intracellular signaling pathways. We also study the mechanism by which transient receptor potential (TRP) channels sense changes in temperature, a mechanism that is critical for their biological roles in thermoregulation and detection of noxious stimuli. Studies with tarantula toxins and regulatory ion binding sites point to a critical role of the external pore in the gating mechanisms of TRPV1, and we are working to localize the temperature sensor and understand its mechanism. Our efforts to understand the structure and operational mechanisms of ligand-activated ion channels involved in intercellular communication has focused on P2X receptor channels, a family of trimeric cation channels that are activated by extracellular ATP. Thus far we have explored the structure and dynamics of the pore, and investigated whether the pore undergoes dilation in response to continual activation. We are currently exploring two distinct mechanisms by which divalent cations differentially regulate P2X receptors, either by binding along with ATP and determining the forms of ATP that serve as agonists, or by binding within an unusual chamber within the large extracellular domain to regulate the process of opening or desensitization.

Staff Image
  • Chanhyung Bae, Ph.D.
    Research Fellow, Contractor

  • Angela Ballesteros Morcillo, Ph.D.
    Research Fellow

  • Tsg-Hui (Helena) Chang, M.Sc
    Laboratory Manager

  • Ana Fernandez-Marino, Ph.D.
    Research Fellow

  • Kanchan Gupta, Ph.D.
    Research Fellow, Contractor

  • Kate Huffer, B.S.
    Graduate Student

  • Andres Jara-Oseguera, Ph.D.
    Research Fellow

  • Mufeng Li, Ph.D.
    Staff Scientist

  • Suvendu Lomash, Ph.D.
    Research Fellow

  • Shai Silberberg, Ph.D.
    Adjunct Investigator

  • Gil Toombes, Ph.D.
    Staff Scientist

  • Xiaosa Wu, Ph.D.
    Postdoctoral Fellow

  • 1) Papp F, Lomash S, Szilagyi O, Babikow E, Smith J, Chang TH, Bahamonde MI, Toombes GES, Swartz KJ (2019)
  • TMEM266 is a functional voltage sensor regulated by extracellular Zn2+
  • eLife, 8, e42372
  • 2) Zhang F, Swartz KJ, Jara-Oseguera A (2019)
  • Conserved allosteric pathways for activation of TRPV3 revealed through engineering vanilloid-sensitivity
  • eLife, 8, e42756
  • 3) Bae C, Jara-Oseguera A, Swartz KJ (2018)
  • TRPM channels come into focus
  • Science, 359, 160-161
  • 4) Matthies D, Bae C, Toombes GE, Fox T, Bartesaghi A, Subramaniam S, Swartz KJ (2018)
  • Single-particle cryo-EM structure of a voltage-activated potassium channel in lipid nanodiscs
  • eLife, 7, :e37558
  • 5) Ballesteros A, Fenollar-Ferrer C, Swartz KJ (2018)
  • Structural relationship between the putative hair cell mechanotransduction channel TMC1 and TMEM16 proteins
  • eLife, 7, e38433
  • 6) Zhang F, Jara-Oseguera A, Chang TH, Bae C, Hanson SM, Swartz KJ (2018)
  • Heat activation is intrinsic to the pore domain of TRPV1
  • Proc Natl Acad Sci, 115(2), E317-E324
  • 7) Toombes, G.E.S. and Swartz, K.J. (2016)
  • Twists and turns in gating ion channels with voltage
  • Science, 353, 646-7
  • 8) Zhang, F, Hanson, SM, Jara-Oseguera, A, Krepkiy, D, Bae, C, Pearce, LV, Blumberg, PM, Newstead, S and Swartz, KJ (2016)
  • Engineering vanilloid-sensitivity into the rat TRPV2 channel
  • eLife, 5
  • 9) Jara-Oseguera, A., Bae, C., and Swartz, K. J. (2016)
  • An external sodium ion binding site controls allosteric gating in TRPV1 channels
  • eLife, 5
  • 10) Bae, C., Anselmi, C., Kalia, J., Jara-Oseguera, A., Schwieters, C. D., Krepkiy, D., Won Lee, C., Kim, E. H., Kim, J. I., Faraldo-Gomez, J. D., and Swartz, K. J. (2016)
  • Structural insights into the mechanism of activation of the TRPV1 channel by a membrane-bound tarantula toxin
  • eLife, 5
  • 11) Gupta, K, Zamanian, M, Bae, CH, Milescu, M, Krepkiy, D, Tilley, D, Sack, J, Yarov-Yarovoy, V, Kim, JI and Swartz, KJ (2015)
  • Tarantula toxins use common surfaces for interacting with Kv and ASIC ion channels
  • eLife, May 7;4:e06774
  • 12) Li, M, Toombes, GES, Silberberg, SD and Swartz, KJ (2015)
  • Physical basis of apparent pore-dilation of ATP-activated P2X receptor channels
  • Nature Neuroscience, advance online Sept 21, 2015, .
  • 13) Mihailescu, M., Krepkiy, D., Milescu, M., Gawrisch, K., Swartz, K.J. and White, S.H. (2014)
  • Structural interactions of a voltage sensor toxin with lipid membranes
  • Proc Nat'l Acad Sci, 111, E5463-70
  • 14) Toombes, E.S. and Swartz, K.J. (2014)
  • Divining the design principles of voltage sensors
  • J Gen Physiol
  • 15) Heymann, G., Dai, J., Li, M., Silberberg, S.D., Zhou, H-X. and Swartz, K.J. (2013)
  • Inter- and intrasubunit interactions between transmembrane helices in the open state of P2X receptor channels
  • Proc Nat'l Acad Sci
  • 16) Kalia, J. and Swartz, K.J. (2013)
  • The design principle of paddle motifs in voltage sensors
  • Nature Struct Mol Biol, 20, 534-5
  • 17) Milescu, M., Lee, H.W., Bae, C., Kim, J.I. and Swartz, K.J. (2013)
  • Opening the Shaker Kv channel with hanatoxin
  • J Gen Physiol, 141, 203-16
  • 18) Li, M., Silberberg, S.D. and Swartz, K.J. (2013)
  • Subtype-specific control of P2X receptor channel signaling by ATP and magnesium
  • Proc Nat'l Acad Sci, 110, E3455-63
  • 19) Kalia, J. and Swartz, K.J. (2013)
  • Common principles of voltage-dependent gating in Hv and Kv channels
  • Neuron, 77, 214-16
  • 20) Swartz KJ (2013)
  • The scorpion toxin and the potassium channel
  • eLife, May 21;2:e00873
  • 21) Krepkiy, D., Gawrisch, K. and Swartz K.J. (2012)
  • Structural interactions between lipids, water and S1-S4 voltage-sensing domains
  • J Mol Biol, 423, 632-647
  • 22) Li, M, Kawate, T, Silberberg, S and Swartz, KJ (2010)
  • Pore-opening mechanism in trimeric P2X receptor channels
  • Nature Communications, 1, 44
  • 23) Krepkiy, D., Mihailescu, M., Freites, J.A., Schow, E., Worcester, D.L., Gawrisch, K., Tobias, D., White, S.H., and Swartz, K.J. (2009)
  • Structure and hydration of membranes embedded with voltage-sensing domains
  • Nature, 462, 473-479
  • 24) Milescu, M., Bosmans, F., Lee, S., Alabi, A.A., Kim, J.I. and Swartz, K.J. (2009)
  • Interaction between lipids and voltage sensor paddles detected with tarantula toxins
  • Nature Structural and Molecular Biology, 16, 1080-1085
  • 25) Swartz, K.J. (2008)
  • Sensing voltage across lipid membranes
  • Nature, 456, 891-897
  • 26) Phillips, L.R., Milescu, M., Li-Smerin, Y., Mindell, J., Kim, J.I. and Swartz, K.J. (2005)
  • Voltage-sensor activation with a tarantula toxin as cargo
  • Nature, 436, 857-860
  • 27) Li M, Wang Y, Banerjee R, Marinelli F, Silberberg SD, Faraldo-Gómez JD, Hattori M and Swartz KJ (2019)
  • Molecular mechanisms of P2X3 receptor channel activation and modulation by divalent cation bound ATP
  • eLife, (in revision)
  • 28) Kalia, J and Swartz, KJ (2013)
  • Exploring structure-function relationships between TRP and Kv channels
  • Sci Reports, 1.182638889, 9-Jan
  • 29) Lee C.W., Bae C., Lee J., Ryu J.H., Kim H.H., Kohno T., Swartz K.J., Kim J.I. (2012)
  • Solution structure of kurtoxin: a gating modifier selective for Cav3 voltage-gated calcium channels
  • Biochemistry, 51, 1862-73
  • 30) Bae, C.H., Kalia, J., Song, I., Yu, J.H., Kim, H.H., Swartz, K.J. and Kim, J.I. (2012)
  • High yield production and refolding of the double-knot toxin, an activator of TRPV1 channels
  • Plos One, 7, 10-Jan
  • 31) Bosmans, F., Puopolo, M., Martin-Eauclaire, M.F., Bean, B.P. and Swartz, K.J. (2011)
  • Functional properties and toxin pharmacology of a dorsal root ganglion sodium channel viewed through its voltage sensors
  • J Gen Physiol, 138, 59-72
  • 32) Kalia, J and Swartz KJ (2011)
  • Elucidating the molecular basis of action of a classical drug: Guanidine compounds as inhibitors of voltage-gated potassium channels
  • Mol Pharmacol, 80, 1085-95
  • 33) Bosmans, F., Milescu, M. and Swartz, K.J. (2011)
  • Palmitoylation influences the function and pharmacology of sodium channels
  • Proc Nat'l Acad Sci, 108, 20213-18
  • 34) Kawate, T., Robertson, J.L., Li, M., Silberberg, S.D. and Swartz, K.J. (2011)
  • Ion access pathway to the transmembrane pore in P2X receptor channels
  • J Gen Physiol, 137, 579-90
  • 35) Lee CW, Eu YJ, Min HJ, Cho EM, Lee JH, Kim HH, Nah SY, Swartz KJ, Kim JI (2011)
  • Expression and characterization of recombinant kurtoxin, an inhibitor of T-type voltage-gated calcium channels
  • Biochem Biophys Res Commun, 416, 277-82
  • 36) Bosmans, F. and Swartz, K.J. (2010)
  • Targeting voltage sensors in sodium channels with spider toxins
  • Trends in Pharmacol. Sci., 31, 175-182
  • 37) Lee, S, Milescu, M, Jung, HH, Lee, JY, Bae, CH, Lee, CW, Kim, HH, Swartz, KJ and Kim, JI (2010)
  • Solution structure of GxTX-1E, a high-affinity tarantula toxin interacting with voltage senors in Kv2.1 potassium channels
  • Biochemistry, 49, 5134-42
  • 38) Jung, HH, Jung, HJ, Milescu, M, Lee, CW, Lee, S, Lee, JY, Eu, YJ, Kim, HH, Swartz, KJ and Kim, JI (2010)
  • Structure and orientation of a voltage-sensor toxin in lipid membranes
  • Biophysical J, 99, 638-46
  • 39) Phillips, L.R. and Swartz, K.J. (2010)
  • Position and motions of the S4 helix during opening of the Shaker potassium channel
  • J Gen Physiol, 136, 629-44
  • 40) Silberberg, S.D. and Swartz, K.J. (2009)
  • Structural Biology - Trimeric ion channel design (News and Views)
  • Nature, 460, 580-581
  • 41) Li, M., Chang, T-H., Silberberg, S.D. and Swartz, K.J. (2008)
  • Gating the pore of P2X receptor channels.
  • Nature Neuroscience, 11, 883-887
  • 42) Bosmans, F., Martin-Eauclaire, M.F. and Swartz, K.J. (2008)
  • Deconstructing voltage sensor function and pharmacology in sodium channels
  • Nature, 456, 202-208
  • 43) Alabi, A.A., Bahamonde, M.I., Jung, H.J., Kim, J.I., and Swartz, K.J. (2007)
  • Portability of paddle motif function and pharmacology in voltage sensors
  • Nature, 450, 370-375
  • 44) Milescu, M., Vobecky, J., Roh, S.H., Kim, S.H., Jung, H.J., Kim, J.I. and Swartz, K.J. (2007)
  • Tarantula toxins interact with voltage sensors within lipid membranes
  • J Gen Physiol, 130, 497-511
  • 45) Silberberg, S.D, Li, M. and Swartz, K.J. (2007)
  • Ivermectin interaction with transmembrane helices reveals widespread rearrangements during opening of P2X receptor channels
  • Neuron, 54, 263-274
  • 46) Swartz KJ (2007)
  • Tarantula toxins interacting with voltage sensors in potassium channels
  • Toxicon, 49, 213-230
  • 47) Soler-Llavina, G., Chang, T. and Swartz, K.J. (2006)
  • Functional interactions at the interface between voltage sensing and pore domains in the Shaker Kv channel
  • Neuron, 52, 623-634
  • 49) Jung, H.J., Lee, J.Y., Kim, S.H., Eu, Y.-J., Shin, S.Y., Milescu, M., Swartz, K.J. and Kim, J.I. (2005)
  • Solution structure and lipid membrane partitioning of VSTx1, an inhibitor of the KvAP potassium channel
  • Biochemistry, 44, 6015-6023
  • 50) Silberberg, S.D., Chang, T.H. and Swartz, K.J. (2005)
  • Secondary structure and gating rearrangements of transmembrane segments in rat P2X4 receptor channels
  • J. General Physiology, 125, 347-359
  • 51) Swartz, K.J. (2005)
  • Structure and anticipatory movements of the S6 Gate in Kv channels (Commentary)
  • J. General Physiology, 126, 413-417
  • 52) Kitaguchi, T. and Swartz, K.J. (2005)
  • An inhibitor of TRPV1 channels isolated from funnel web spider venom
  • Biochemistry, 44, 15544-15549
  • 55) Wang, J.M., Roh, S.H., Kim, S., Lee, C.W., Kim, J.I. and Swartz, K.J. (2004)
  • Molecular surface of tarantula toxins interacting with voltage-sensors in Kv channels
  • J. General Physiology, 123, 455-467
  • 56) Kitaguchi, T., Sukhareva, M. and Swartz, K.J. (2004)
  • Stabilizing the closed gate in the Shaker Kv channel through modification of a hydrophobic seal
  • J. General Physiology, 124, 319-332
  • 57) Lee, C.W., Kim, S., Roh, S.H., Endoh, H., Kodera, Y., Maeda, T., Kohno, T., Wang, J.M., Swartz, K.J. and Kim, J.I. (2004)
  • Solution structure and functional characterization of SGTx1, a modifier of Kv2.1 channel gating
  • Biochemistry, 43, 890-897
  • 58) Soler-Llavina, G., Holmgren, M. and Swartz, K.J. (2003)
  • Defining the conductance of the closed state in a voltage-gated potassium channel
  • Neuron, 38, 61-67
  • 59) Lee, H.C., Wang, L.M. and Swartz, K.J. (2003)
  • Interaction between extracellular Hanatoxin and the resting conformation of the voltage-sensor paddle in Kv channels
  • Neuron, 40, 527-536
  • 60) Sukhareva, M., Hackos, D. and Swartz, K.J. (2003)
  • Constitutive activation of the Shaker Kv channel
  • J. General Physiology, 122, 541-556
  • 61) Hackos, D.H, Chang, T.H. and Swartz, K.J. (2002)
  • Scanning the intracellular S6 activation gate in the Shaker potassium channel
  • J. General Physiology, 119, 521-531
  • 62) Takeuchi, K., Park, E., Lee, C., Kim, J., Takahashi, H., Swartz, K. & Shimada, I. (2002)
  • Solution structure of omega-grammotoxin SIA, a gating modifier of P/Q and N-type calcium channel.
  • J. Molecular Biology, 321, 517-526
  • 63) Li-Smerin, Y. and Swartz, K.J. (2001)
  • Helical structure of the COOH-terminus of S3 and its contribution to the gating modifier toxin receptor in voltage-gated ion channels
  • J. General Physiology, 117, 205-217
  • 64) Li-Smerin, Y., Hackos, D.H. and Swartz, K.J. (2000)
  • alpha-Helical structural elements within the voltage-sensing domains of a potassium channel
  • J. General Physiology , 115, 33-49
  • 65) Li-Smerin, Y. and Swartz, K.J. (2000)
  • Localization and molecular determinants of the hanatoxin receptors on the voltage-sensing domain of a potassium channel
  • J. General Physiology, 115, 673-684
  • 66) Takahashi, H., Kim, J.I., Min, H.J., Sato, K., Swartz, K.J. and Shimada, I. (2000)
  • Solution structure of hanatoxin1, a gating modifier of voltage-dependent potassium channels: common surface features of gating modifier toxins
  • J. Molecular Biology, 297, 771-780
  • 67) Li-Smerin, Y., Hackos, D.H. and Swartz, K.J. (2000)
  • A localized interaction surface for voltage-sensing domains on the pore domain of a potassium channel
  • Neuron, 25, 411-423
  • 68) Winterfield, J.R. and Swartz, K.J. (2000)
  • A hot spot for the interaction of gating modifier toxins with voltage-dependent ion channels
  • J. General Physiology, 116, 637-644
  • 69) Li-Smerin, Y. and Swartz, K.J. (1998)
  • Gating modifier toxins reveal a conserved structural motif in voltage-gated calcium and potassium channels
  • Proc. Natl. Acad. Sci. (USA) , 95, 8585-8589
  • 70) Chuang, R. S-I., Jaffe, H., Cribbs, L., Perez-Reyes, E., and K.J. Swartz (1998)
  • Inhibition of T-type voltage-gated calcium channels by a new scorpion toxin
  • Nature Neuroscience, 1, 668-674
  • 71) Swartz, K.J. and MacKinnon, R. (1997)
  • Mapping the receptor site for Hanatoxin, a gating modifier of voltage-dependent potassium channels
  • Neuron, 18, 675-682
  • 72) Swartz, K.J. and MacKinnon, R. (1997)
  • Hanatoxin modifies the gating of a voltage-gated potassium channel through multiple binding sites.
  • Neuron, 18, 665-673
  • 73) McDonough, S.I., Swartz, K.J., Mintz, I.M., Boland, L.M. and Bean, B.P. (1996)
  • Inhibition of calcium channels in rat central and peripheral neurons by w-conotoxin-MVIIC
  • J. Neuroscience, 16, 2612-2623
  • 74) Swartz, K.J. and MacKinnon, R. (1995)
  • An inhibitor of the Kv2.1 potassium channel isolated from the venom of a Chilean tarantula
  • Neuron, 15, 941-949
  • 75) Swartz, K.J., Merritt, A., Bean, B.P. and Lovinger, D.M. (1993)
  • Protein kinase C modulates glutamate receptor inhibition of calcium channels and synaptic transmission
  • Nature, 361, 165-168
  • 76) Swartz, K.J. (1993)
  • Modulation of calcium channels by protein kinase C in rat central and peripheral neurons: disruption of G protein-mediated inhibition
  • Neuron, 11, 305-320
  • 77) Swartz, K.J., Koroshetz, W.J., Rees, A.H. and Huettner, J.E. (1992)
  • Competitive antagonism of glutamate receptor channels by substituted benzazepines in cultured cortical neurons
  • Molecular Pharmacology, 41, 1130-1141
  • 78) Swartz, K.J. and Bean, B.P. (1992)
  • Inhibition of calcium channels in rat CA3 pyramidal neurons by a metabotropic glutamate receptor
  • J. Neuroscience, 12, 4358-4371
  • 79) Swartz, K.J., Matson, W.R., MacGarvey, U.M., Ryan, E.A. and Beal, M.F. (1990)
  • Measurement of kynurenic acid in mammalian brain extracts and cerebralspinal fluid by high-performance liquid chromatography with fluorometric and coulometric electrode array detection
  • Analytical Biochemistry , 185, 363-376
  • 80) Swartz, K.J., During, M.J., Freese, A. and Beal, M.F (1990)
  • Cerebral synthesis and release of kynurenic acid: an endogenous antagonist of excitatory amino acid receptors
  • J. Neuroscience , 10, 2965-2973
  • 81) Barres, B.A., Koroshetz, W.J., Swartz, K.J., Chun, L.L.Y. and Corey, D.P. (1990)
  • Ion channel expression by white matter glia: the O-2A glial progenitor cell
  • Neuron, 4, 507-524
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