Virtually all ion channels in the nervous system are members of multigene families. This abundance of genes results in a remarkable molecular diversity of both voltage-gated and ligand-gated ion channels. We are using a multidisciplinary approach to study sodium channels (NaChs) which underlie electrical signaling in the nervous system. The proposed research has two goals: (1) to continue identifying and characterizing novel NaCh genes and (2) later to test possible physiological roles subserved by these NaCh subtypes. We estimate that rats (like humans) have at least ten NaCh genes. We have isolated and are characterizing one full-length cDNA and one partial cDNA for novel NaChs. One cDNA is the most abundant NaCh in brain and is expressed in both neurons and glia. The second NaCh is probably expressed only in the peripheral nervous system. We are using a variety of molecular, cellular, and biophysical techniques to study the distribution, abundance, and electrophysiological properties of these NaChs. The second goal centers around a question which has not been answered for any ion channel: why are there so many genes? A simple answer is that all subtypes have similar channel properties but specialized roles. The above studies provide a basis for testing hypothetical roles for these NaCh subtypes. Two functions will be tested: preferential targeting to different cellular domains and differential modulation by second messenger systems. These studies will contribute to our understanding of the molecular components and cellular regulation of Na currents. They also will provide an important foundation for understanding human neural and muscular diseases. Known mutations in the human adult skeletal muscle NaCh gene produce hyperexcitability and sometimes temporary paralysis. It is expected that mutations also occur in the other NaCh genes, most of which are expressed in the nervous system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS026505-06A1
Application #
2265965
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1989-08-01
Project End
1999-02-28
Budget Start
1995-04-01
Budget End
1996-02-29
Support Year
6
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Biology
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Young, Katharine A; Caldwell, John H (2005) Modulation of skeletal and cardiac voltage-gated sodium channels by calmodulin. J Physiol 565:349-70
Boiko, Tatiana; Van Wart, Audra; Caldwell, John H et al. (2003) Functional specialization of the axon initial segment by isoform-specific sodium channel targeting. J Neurosci 23:2306-13
Schaller, Kristin L; Caldwell, John H (2003) Expression and distribution of voltage-gated sodium channels in the cerebellum. Cerebellum 2:2-9
Boiko, T; Rasband, M N; Levinson, S R et al. (2001) Compact myelin dictates the differential targeting of two sodium channel isoforms in the same axon. Neuron 30:91-104
Krzemien, D M; Schaller, K L; Levinson, S R et al. (2000) Immunolocalization of sodium channel isoform NaCh6 in the nervous system. J Comp Neurol 420:70-83
Schaller, K L; Caldwell, J H (2000) Developmental and regional expression of sodium channel isoform NaCh6 in the rat central nervous system. J Comp Neurol 420:84-97
Caldwell, J H; Schaller, K L; Lasher, R S et al. (2000) Sodium channel Na(v)1.6 is localized at nodes of ranvier, dendrites, and synapses. Proc Natl Acad Sci U S A 97:5616-20
Reese, K A; Caldwell, J H (1999) Immunocytochemical localization of NaCh6 in cultured spinal cord astrocytes. Glia 26:92-6
Sharp, A A; Caldwell, J H (1996) Aggregation of sodium channels induced by a postnatally upregulated isoform of agrin. J Neurosci 16:6775-83
Lupa, M T; Krzemien, D M; Schaller, K L et al. (1995) Expression and distribution of sodium channels in short- and long-term denervated rodent skeletal muscles. J Physiol 483 ( Pt 1):109-18

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