Propagation of electrical signals with high speed and reliability in nerve fibers depends on a complex interaction between neurons and their associated myelinating glial cells. As a result of this interaction ion channels are clustered at specific sites along the axon. This system is studied in both development and disease. At birth axons have little myelin, but by the end of the first postnatal week both glial ensheathment and ion channel clustering are at an advanced state. In multiple sclerosis myelin is damaged, and ion channel distributions are disrupted. The immune mechanisms responsible for this pathology are not known. This laboratory studies the molecular mechanisms responsible for these phenomena using electrophysiology, immunocytochemistry, molecular biology, and transgenic manipulations. During myelination glial cells have a profound influence on the axonal ion channel distribution. In the peripheral nervous system Schwann cells bind to axons during both development and remyelination. Sodium channels, responsible for the upstroke of the action potential, cluster in the axon membrane adjacent to the tips of Schwann cell processes that are extended during early stages of ensheathment. As Schwann cells grow longitudinally, these channels appear to move with them, ultimately fusing with a neighboring cluster to form a node of Ranvier. Voltage-dependent potassium channels have a reciprocal relationship with sodium channels, and are located primarily in clusters several micrometers on either side of the node. New studies are focused on the central nervous system and combine immunocytochemistry with electrophysiology to determine the distribution and role of ion channels during development of the optic nerve. We seek to determine the cellular and molecular events responsible for ion channel localization and stabilization in the neuronal membrane. For a more complete description of projects in this laboratory, go to: Shrager Lab.

Xu, X. and Shrager, P. 2005. Dependence of axon initial segment formation on Na+ channel expression. Journal of Neuroscience Research 79:428-441

Taveggia, C., Zanazzi, G., Petrylak, A., Yano, H., Rosenbluth, J., Einheber, S., Xu, X., Esper, R. M., Loeb, J. A., Shrager, P., Chao, M. V., Falls, D. L., Role, L., Salzer J. L. 2005. Type III Neuregulin-1 levels determine the ensheathment fate of axons. Neuron 47:681-694.

Chen, C., Westenbroek, R. E., Xu, X., Edwards, C. A., Sorenson, D. R., Chen, Y., McEwen, D. P., O'Malley, H. A., Bharucha, V., Meadows, L. S., Knudsen, G. A., Vilaythong, A., Noebels, J. L., Saunders, T. L., Scheuer, T., Shrager, P., Catterall, W. A. and Isom, L. L. 2004. Mice lacking sodium channel beta1 subunits display defects in neuronal excitability, sodium channel expression, and nodal architecture. Journal of Neuroscience 24: 4030-4042.

Kazarinova-Noyes, K. and Shrager, P. 2002. Molecular constituents of the node of Ranvier. Molecular Neurobiology 26:167-182

Chen, C, Bharucha, V, Chen, Y, Westenbroek, RE, Brown, A, Malhotra, JD, Jones, D, Avery, C, Gillespie, PJ, Kazen-Gillespie, KA, Kazarinova-Noyes, K, Shrager, P, Saunders, TL, Macdonald, RL, Ransom, BR, Scheuer, T, Catterall, WA, and Isom, LL. 2002. Reduced sodium channel density, altered voltage dependence of inactivation, and increased susceptibility to seizures in mice lacking sodium channel beta2-subunits. Proceedings of the National Academy of Sciences 99: 17072-17077.

Zhang, CL, J.X. Connor,K. McCormack, X. Xu, P. Shrager, A. Messing and S.Y. Chiu. 2002

Mutations in Kv-beta2 and Kv1.1 alter mammalian optic nerve excitability. Abstracts, Society for Neuroscience.

Bergstrom, U, E.O. Berglund, K. Kazarinova-Noyes, E. Peles, P.J. Brophy, P. Shrager, B. Ranscht. 2002 Contactin supports the organization of central paranodal junctions. Abstracts, Society for Neuroscience.

Chen, C, Y. Chen, R.E. Westenbroek, X. Xu, H.A. O'Malley, T.L. Saunders, P. Shrager, T. Scheuer, W.A. Catterall, L.L. Isom. 2002 Sodium Channel beta1 (-/-) Mice. Abstracts, Society for Neuroscience

Kazarinova-Noyes, K., Malhotra, J.D., McEwen, D.P., Mattei, L.N., Berglund, E.O., Ranscht, B., Levinson, S.R., Schachner, M., Shrager, P., Isom, L.L., Xiao, Z.C. 2001, Contactin associates with Na⁺ channels and increases their functional expression. J. Neurosci.,21: 7517-7525.

Rasband, M.N., Trimmer, J.S., Peles, E., Levinson, S.R., and Shrager, P 2000, K⁺ channel distribution and clustering in developing and hypomyelinated axons of the optic nerve. J. Neurocytol., 28: 319-331.

Harroch, S., Palmeri, M., Rosenbluth, J., Custer, A., Okigaki, M., Shrager, P., Blum, M., Buxbaum, J.D., and Schlessinger, J. 2000, No obvious abnormality in mice deficient in receptor protein tyrosine phosphatase beta. Molecular and Cellular Biology, 20:7706-7715.

Rasband, M.N., Peles, E., Trimmer, J.S., Levinson, S.R., Lux, S.E., and Shrager, P. 1999, Dependence of nodal sodium channel clustering on paranodal axoglial contact in the developing central nervous system. J. Neurosci. 19:7516-7528.

Vabnick, I., Trimmer, J.S., Schwarz, T.L., Levinson, S.R., Risal, D. and Shrager, P. 1999, Dynamic potassium channel distributions during axonal development prevent aberrant firing patterns. J. Neurosci. 19:747-758.

Rasband, M.N. and Shrager, P. 2000, Ion channel sequestration in central nervous system axons. J. Physi. 525, 1: 63-73.