Molecular Neurophysiology Section - Division of Intramural Research

Miguel Holmgren, Ph.D., Senior Investigator

Laboratory Staff

Angel de la Cruz, B.Sc., Doctoral Student
Angelica Maria Lopez, Ph.D., Visiting Fellow
Chhavi Mathur, Ph.D., Postdoctoral Fellow
Pablo Miranda, Ph.D., Postdoctoral Fellow
Deepa Srikumar, M.Sc, Research Assistant
Gaurav Venkataraman, B.S., Postbaccalaureate IRTA

Research Interests

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.

Selected Recent Publications

• Lopez-Rodriguez A, Holmgren M
  Restoration of proper trafficking to the cell surface for membrane proteins harboring cysteine mutations. , PLoS One., 2012, vol. 2012;7(10), pp. e47693. Full Text/Abstract
• Gadsby, D.C., Bezanilla, F., Rakowski, R.F., De Weer, P. and Holmgren
  The dynamic relationships between the three events that release individual Na+ ions from the Na+/K+-ATPase, Nature Communications, 2012, vol. 3, pp. 669 doi:1038/ncomms1673. Full Text/Abstract
• Castillo J.P., De Giorgis D., Basilio, D., Gadsby, D.C., Rosenthal, J.J., Latorre, R., Holmgren, M., Bezanilla,
  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, 2011, vol. 108, pp. 20556-20561. Full Text/Abstract
• Gonzalez, C., Lopez-Rodriguez, A., Srikumar, D., Rosenthal, J.J.C. and Holmgren, M.
  Editing of human KV1.1 channel mRNAs disrupts binding of the N-terminus tip at the intracellular cavity., Nat. Commun., 2011, vol. 2, pp. 436 doi: 10.1038/ncomms1446. Full Text/Abstract
• Sandtner, W., Egwolf, B., Khalili-Araghi, F., Sanchez-Rodriguez, J.E., Roux, B., Bezanilla, F. and Holmgren, M.
  Ouabain binding site in a functioning Na+/K+-ATPase. , J. Biol. Chem., 2011, vol. 286, pp. 38177-38183.. Full Text/Abstract
• Galarza, G. Soto, S.I., Holmgren M. and Rosenthal, J.J.C
  Physiological Adaptation of an Antarctic Na+/K+-ATPase to the cold., J. Exp. Biol., 2011, vol. 214, pp. 2164-2174. Full Text/Abstract
• Colina, C., Palavicini, J.P., Srikumar, D., Holmgren, M. and Rosenthal, J.J.C
  Regulation of Na+/K+ ATPase transport velocity by RNA editing., PLoS Biol., 2010, vol. 8, pp. e1000540. Full Text/Abstract
• Contreras, J.E., Chen, J., Lau, A.Y., Jogini, V., Roux, B. and Holmgren, M
  Voltage profile along the permeation pathway of an open channel., Biophys. J., 2010, vol. 99, pp. 2863-2869. Full Text/Abstract

Selected Earlier Publications

Contact Information

Molecular Neurophysiology Section, NINDS
Porter Neuroscience Research Center
Building 35 Room 3B-1016
35 Convent Drive, MSC 3701
Bethesda, MD 20892-3701

Telephone: 301-451-6259 (office), 301-451-6258 (laboratory), 301-496-4268 (fax)
Email: holmgren@ninds.nih.gov