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The Journal of Neuroscience, October 24, 2007, 27(43):11533-11542; doi:10.1523/JNEUROSCI.5005-06.2007

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Cellular/Molecular
Regulation of Na_V1.2 Channels by Brain-Derived Neurotrophic Factor, TrkB, and Associated Fyn Kinase

Misol Ahn, ^* Daniel Beacham, ^* Ruth E. Westenbroek, Todd Scheuer, and William A. Catterall

Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280

Correspondence should be addressed to William A. Catterall, Department of Pharmacology, Mail Stop 357280, University of Washington, Seattle, WA 98195-7280. Email: wcatt{at}u.washington.edu

Voltage-gated sodium channels are responsible for action potential initiation and propagation in neurons, and modulation of their function has an important impact on neuronal excitability. Sodium channels are regulated by a Src-family tyrosine kinase pathway, and this modulation can be reversed by specifically bound receptor phosphoprotein tyrosine phosphatase-ß. However, the specific tyrosine kinase and signaling pathway are unknown. We found that the sodium channels in rat brain interact with Fyn, one of four Src-family tyrosine kinases expressed in the brain. Na_V1.2 channels and Fyn are localized together in the axons of cultured hippocampal neurons, the mossy fibers of the hippocampus, and cell bodies, dendrites, and axons of neurons in many other brain areas, and they coimmunoprecipitate with Fyn from cotransfected tsA-201 cells. Coexpression of Fyn with Na_V1.2 channels decreases sodium currents by increasing the rate of inactivation and causing a negative shift in the voltage dependence of inactivation. Reconstitution of a signaling pathway from brain-derived neurotrophic factor (BDNF) to sodium channels via the tyrosine receptor kinase B (TrkB)/p75 neurotrophin receptor and Fyn kinase in transfected cells resulted in an increased rate of inactivation of sodium channels and a negative shift in the voltage dependence of inactivation after treatment with BDNF. These results indicate that Fyn kinase is associated with sodium channels in brain neurons and can modulate Na_V1.2 channels by tyrosine phosphorylation after activation of TrkB/p75 signaling by BDNF.

Key words: sodium channel; Fyn; tyrosine kinase; tyrosine phosphorylation; neuromodulation; neurotrophin

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Received Nov. 17, 2006; revised July 16, 2007; accepted July 17, 2007.

Correspondence should be addressed to William A. Catterall, Department of Pharmacology, Mail Stop 357280, University of Washington, Seattle, WA 98195-7280. Email: wcatt{at}u.washington.edu

This article has been cited by other articles:

				T. K. Aman, T. M. Grieco-Calub, C. Chen, R. Rusconi, E. A. Slat, L. L. Isom, and I. M. Raman Regulation of Persistent Na Current by Interactions between {beta} Subunits of Voltage-Gated Na Channels J. Neurosci., February 18, 2009; 29(7): 2027 - 2042. [Abstract] [Full Text] [PDF]

				Y. H. Zhang, X. X. Chi, and G. D. Nicol Brain-derived neurotrophic factor enhances the excitability of rat sensory neurons through activation of the p75 neurotrophin receptor and the sphingomyelin pathway J. Physiol., July 1, 2008; 586(13): 3113 - 3127. [Abstract] [Full Text] [PDF]

				D. Beacham, M. Ahn, W. A. Catterall, and T. Scheuer Sites and Molecular Mechanisms of Modulation of NaV1.2 Channels by Fyn Tyrosine Kinase J. Neurosci., October 24, 2007; 27(43): 11543 - 11551. [Abstract] [Full Text] [PDF]

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