The threshold for action potential generation and the frequency of firing of central neurons depend critically on the cell surface density, localization, and functional properties of Na channels. Control of the cell surface density and localization of Na channels is a critical aspect of neuronal function. Previous results suggest that assembly, cell surface insertion, and differential targeting of Na channel subtypes all play important roles in this process. Cloning and functional analysis of the Beta1 and Beta2 subunits of brain Na channels have implicated these two proteins in modulation of Na channel gating, assembly of functional channels, and expression and localization of Na channels on the cell surface. In addition, the immunoglobulinlike folds in the extracellular domains of the Beta subunits suggest that they function as cell adhesion molecules. In our recent research, we have defined the new structural requirements for modulation of gating by the Beta1 subunit, discovered novel protein-protein interactions of Beta subunits with the extracellular matrix protein tenascin, the cell adhesion molecule neurofascin, and the transmembrane receptor phosphoprotein tyrosine phosphatase Beta, and analyzed the functional roles of Beta subunits in vivo in mice with disrupted 13 subunit genes. In the next project period, we plan to identify the molecular determinants for functional interaction of Na channel a and Beta subunits, investigate the molecular determinants for interaction of Na channel Beta subunits with cell adhesion and extracellular matrix molecules, define the molecular basis for regulation of Na channels by associated protein tyrosine kinases and phosphoprotein tyrosine phosphatases., identify novel molecular components of Na channel signaling complexes and determine their functional role, and examine the functional role of Na channel Beta subunits and signaling complexes in vivo in genetically altered mice. Our results will add substantially to understanding of the cell biology of the Na channel and the functional significance of Na channel signaling complexes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS025704-19
Application #
7083685
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Silberberg, Shai D
Project Start
1988-02-01
Project End
2008-09-29
Budget Start
2006-06-01
Budget End
2008-09-29
Support Year
19
Fiscal Year
2006
Total Cost
$351,589
Indirect Cost
Name
University of Washington
Department
Pharmacology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Catterall, William A (2018) Dravet Syndrome: A Sodium Channel Interneuronopathy. Curr Opin Physiol 2:42-50
Rubinstein, M; Patowary, A; Stanaway, I B et al. (2018) Association of rare missense variants in the second intracellular loop of NaV1.7 sodium channels with familial autism. Mol Psychiatry 23:231-239
Kaplan, Joshua S; Stella, Nephi; Catterall, William A et al. (2017) Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome. Proc Natl Acad Sci U S A 114:11229-11234
Catterall, William A (2017) Forty Years of Sodium Channels: Structure, Function, Pharmacology, and Epilepsy. Neurochem Res 42:2495-2504
Catterall, William A (2015) Finding Channels. J Biol Chem 290:28357-73
Kalume, Franck; Oakley, John C; Westenbroek, Ruth E et al. (2015) Sleep impairment and reduced interneuron excitability in a mouse model of Dravet Syndrome. Neurobiol Dis 77:141-54
Rubinstein, Moran; Westenbroek, Ruth E; Yu, Frank H et al. (2015) Genetic background modulates impaired excitability of inhibitory neurons in a mouse model of Dravet syndrome. Neurobiol Dis 73:106-17
Rubinstein, Moran; Han, Sung; Tai, Chao et al. (2015) Dissecting the phenotypes of Dravet syndrome by gene deletion. Brain 138:2219-33
Catterall, William A (2014) Sodium channels, inherited epilepsy, and antiepileptic drugs. Annu Rev Pharmacol Toxicol 54:317-38
Baek, Je-Hyun; Rubinstein, Moran; Scheuer, Todd et al. (2014) Reciprocal changes in phosphorylation and methylation of mammalian brain sodium channels in response to seizures. J Biol Chem 289:15363-73

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