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Molecular Neurophysiology Section

Miguel Holmgren, Ph.D.

Senior Investigator

Porter Neuroscience Research Center
Building 35 Room 3B-1016
35 Convent Drive MSC 3701
Bethesda MD 20892-3701
Office: (301) 451-6259
Lab: (301) 451-6258
Fax: (301) 496-4268
holmgren@ninds.nih.gov

Dr. Holmgren received his B.S in 1985 from Universidad Autonoma Metropolitana, Unidad Xochimilco, Ciudad de Mexico. In 1994 he received his Ph.D. in Physiology and Biophysics from Finch University of Health Sciences within the Chicago Medical School, working on the sodium/potassium ATPase with Robert Rakowski. Dr. Holmgren went on to do postdoctoral training with Gary Yellen at Harvard Medical School where he studied the gating mechanisms of voltage-activated potassium channels. He joined the NINDS as an Investigator in 2001. Dr. Holmgren's laboratory is exploring the structure and biophysics of various ion channels and transporters.



Neurons contain a variety of membrane proteins responsible for the continuous traffic of ions and molecules across the cell membrane. Our main goal is to understand how ions are transported through some of these proteins. We are presently interested in ion channels and the sodium/potassium ATPase; the former moving ions at rates near diffusion, while the latter at rates of about 100 per sec. For both types of proteins, we are asking similar questions. How do ions access their pathway? Which regions of the proteins form the permeation pathways that allow ions to move across the membrane? How does the protein regulate the traffic of ions? What are the interactions of molecules like blockers and toxins with these proteins? We attempt to answer these types of questions by combining molecular biology, chemical modification and electrophysiological techniques.

Recently, we have become increasingly interested in understanding how RNA editing alters the function of membrane proteins. RNA editing is a post-transcriptional modification believed to be a major mechanism in acclimatization and/or adaptation. An enzyme converts adenosine into inosine, which is interpreted as guanosine by the cellular machinery. This conversion provides a vast mutagenic repertoire by which critical positions in a protein can be altered. Although, a growing number of mRNA substrates have been shown to be edited, very little is known about the functional consequences of these modifications. We are taking advantage of the apparent high levels of editing in squid to examine RNA editing in a variety of membrane proteins including ion channels and transporters. Studying the regulation of membrane proteins by RNA editing will reveal how nature functionally tunes these proteins, and guide our questions on the structure and function of these important cellular machines.

Staff Image
  • Elke Bocksteins, Ph.D.
    Postdoctoral Visiting Fellow
    Phone : 301-451-6258
    Email : elke.bocksteins@uantwerpen.be

  • Angel de la Cruz, B.Sc.
    Doctoral Student
    Phone :
    Email : angel.delacruzlandrau@nih.gov

  • Angelica Lopez, Ph.D.
    Visiting Fellow
    Phone : (301) 451-6258
    Email : lopezang@ninds.nih.gov

  • Chhavi Mathur, Ph.D.
    Postdoctoral Fellow
    Phone : 301-451-6258
    Email : mathurc@ninds.nih.gov

  • Pablo Miranda, Ph.D.
    Postdoctoral Fellow
    Phone :
    Email : mirandafernanp2@ninds.nih.gov

  • Francisco Palma-Cerda, Ph.D.
    Research Fellow
    Phone : 301-451-6258
    Email : francisco.palma-cerda@nih.gov

  • Deepa Srikumar, M.Sc
    Research Assistant
    Phone : (301) 451-6258
    Email : srikumad@ninds.nih.gov

  • 1) Oelstrom K, Goldschen-Ohm MP, Holmgren M, Chanda B (2014)
  • Evolutionarily conserved intracellular gate of voltage-dependent sodium channels
  • Nature Communications, 5, 3420
  • 2) Venkataraman G, Srikumar D & Holmgren M (2014)
  • Quasi-specific access of the potassium channel inactivation gate.
  • Nat. Commun., 5, 4050
  • 3) Miranda, P, Contreras, JE, Plested, AJR, Sigworth, FJ, Holmgren, M and Giraldez,T (2013)
  • State-dependent FRET reports calcium- and voltagedependent gating-ring motions in BK channels
  • Proc. Nat. Acad. Sci. USA, 110, 5217-5222
  • 4) Lopez-Rodriguez A, Holmgren M (2012)
  • Restoration of proper trafficking to the cell surface for membrane proteins harboring cysteine mutations.
  • PLoS One, 2012;7(10), e47693
  • 5) Gadsby, D.C., Bezanilla, F., Rakowski, R.F., De Weer, P. and Holmgren (2012)
  • The dynamic relationships between the three events that release individual Na+ ions from the Na+/K+-ATPase
  • Nature Communications, 3, 669 doi:1038/ncomms1673
  • 6) Sandtner, W., Egwolf, B., Khalili-Araghi, F., Sanchez-Rodriguez, J.E., Roux, B., Bezanilla, F. and Holmgren, M. (2011)
  • Ouabain binding site in a functioning Na+/K+-ATPase.
  • J. Biol. Chem. , 286, 38177-38183.
  • 7) Galarza, G. Soto, S.I., Holmgren M. and Rosenthal, J.J.C (2011)
  • Physiological Adaptation of an Antarctic Na+/K+-ATPase to the cold.
  • J. Exp. Biol., 214, 2164-2174
  • 8) Castillo J.P., De Giorgis D., Basilio, D., Gadsby, D.C., Rosenthal, J.J., Latorre, R., Holmgren, M., Bezanilla, (2011)
  • Energy landscape of the reactions governing the Na+ deeply occluded state of the Na+/K+-ATPase in the axon of the Humboldt squid.
  • Proc. Nat. Acad. Sci. USA , 108, 20556-20561
  • 9) Gonzalez, C., Lopez-Rodriguez, A., Srikumar, D., Rosenthal, J.J.C. and Holmgren, M. (2011)
  • Editing of human KV1.1 channel mRNAs disrupts binding of the N-terminus tip at the intracellular cavity.
  • Nat. Commun. , 2, 436 doi: 10.1038/ncomms1446
  • 10) Contreras, J.E., Chen, J., Lau, A.Y., Jogini, V., Roux, B. and Holmgren, M (2010)
  • Voltage profile along the permeation pathway of an open channel.
  • Biophys. J., 99, 2863-2869
  • 11) Colina, C., Palavicini, J.P., Srikumar, D., Holmgren, M. and Rosenthal, J.J.C (2010)
  • Regulation of Na+/K+ ATPase transport velocity by RNA editing.
  • PLoS Biol. , 8, e1000540
  • 12) Contreras, J.E. Srikumar, D. and Holmgren, M. (2008)
  • Gating at the selectivity filter in cyclic nucleotide-gated channels
  • PNAS, 105, 3310-3314
  • 13) Rakowski, R.F., P. Artigas, F. Palma, M. Holmgren, P. De Weer, & D.C. Gadsby (2007)
  • Sodium Flux Ratio in Na/K Pump-Channels Opened by Palytoxin
  • Journal of General Physiology, 130, 41-54
  • 14) Colina, C., J.J.C. Rosenthal, J.A. DeGiorgis, D. Srikumar, N. Iruku& M. Holmgren (2007)
  • Structural basis of Na+/K+-ATPase adaptation to marine environments
  • Nature Structural Molecular Biology, 14, 427-431
  • 15) Contreras, JE and Holmgren, M. (2006)
  • Access of quaternary ammonium blockers to the internal pore of cyclic nucleotide-gated channels: implications for the location of the gate.
  • J. Gen. Physiol., 127, 481-94
  • 16) Holmgren, M. and Rakowski, RF. (2006)
  • Charge Translocation by the Na+/K+ Pump under Na+/Na+ Exchange Conditions: Intracellular Na+ Dependence
  • Biophys. J., 90, 1607-16
  • 17) Bhalla, T., Rosenthal, JJC, Holmgren, M., and Reenan, R. (2004)
  • Control of Human Potassium Channel Inactivation by Editing of a Small mRNA Hairpin
  • Nature Structural & Molecular Biology, 11, 950-956
  • 18) Soler-Llavina GJ, Holmgren M, and Swartz KJ (2003)
  • Defining the Conductance of the Closed State in a Voltage-Gated K+ Channel
  • Neuron, 38, 61-67
  • 19) Holmgren, Miguel (2003)
  • Influence of Permeant Ions on Gating in Cyclic Nucleotide-gated Channels
  • J. Gen Physiol, 121, 61-72
  • 20) del Camino D, Holmgren M, Liu Y, Yellen G. (2000)
  • Blocker protection in the pore of a voltage-gated K+ channel and its structural implications
  • Nature, 403(6767), 321-5
  • 21) Holmgren M, Wagg J, Bezanilla F, Rakowski RF, De Weer P and Gadsby DC (2000)
  • Three distinct and sequential steps in the release of sodium ions by the Na+/K+-ATPase
  • Nature, 403(6772), 898-901
  • 22) Holmgren M, Shin KS, Yellen G (1998)
  • The activation gate of a voltage-gated K+ channel can be trapped in the open state by an intersubunit metal bridge
  • Neuron, 21(3), 617-21
  • 23) Liu Y, Holmgren M, Jurman ME, Yellen G. (1997)
  • Gated access to the pore of a voltage-dependent K+ channel
  • Neuron, 19(1), 175-84
  • 24) Holmgren M, Smith PL, Yellen G. (1997)
  • Trapping of organic blockers by closing of voltage-dependent K+ channels: evidence for a trap door mechanism of activation gating
  • J Gen Physiol , 109(5), 527-35
  • 25) Holmgren M, Jurman ME, Yellen G. (1996)
  • N-type inactivation and the S4-S5 region of the Shaker K+ channel
  • :J Gen Physiol , 108(3), 195-206
  • 26) Holmgren M, Liu Y, Xu Y, Yellen G. (1996)
  • On the use of thiol-modifying agents to determine channel topology
  • Neuropharmacology, 35(7), 797-804
  • 27) Holmgren M, Rakowski RF. (1994)
  • Pre-steady-state transient currents mediated by the Na/K pump in internally perfused Xenopus oocytes
  • Biophys J, 66(3 Pt 1), 912-22

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