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The Journal of Neuroscience, October 24, 2007, 27(43):11543-11551; doi:10.1523/JNEUROSCI.1743-07.2007

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Cellular/Molecular
Sites and Molecular Mechanisms of Modulation of Na_V1.2 Channels by Fyn Tyrosine Kinase

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

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 important targets for modulation of electrical excitability by neurotransmitters and neurotrophins acting through protein phosphorylation. Fast inactivation of Na_V1.2 channels is regulated via tyrosine phosphorylation by Fyn kinase and dephosphorylation by receptor phosphoprotein tyrosine phosphatase-ß, which are associated in a signaling complex. Here we have identified the amino acid residues on Na_V1.2 channels that coordinate binding of Fyn kinase and mediate inhibition of sodium currents by enhancing fast inactivation. Fyn kinase binds to a Src homology 3 (SH3)-binding motif in the second half of the intracellular loop connecting domains I and II (L_I–II) of Na_V1.2, and mutation of that SH3-binding motif prevents Fyn binding and Fyn enhancement of fast inactivation of sodium currents. Analysis of tyrosine phosphorylation sites by mutagenesis and functional expression revealed a multisite regulatory mechanism. Y66 and Y1893, which are in consensus sequences appropriate for binding to the Fyn SH2 domain after phosphorylation, are both required for optimal binding and regulation by Fyn. Y730, which is located near the SH3-binding motif in L_I–II, and Y1497 and Y1498 in the inactivation gate in L_III–IV, are also required for optimal regulation. Phosphorylation of these sites likely promotes fast inactivation. Fast inactivation of the closely related Na_V1.1 channels is not modulated by Fyn, and these channels do not contain an SH3-binding motif in L_I–II. Subtype-selective modulation by tyrosine phosphorylation/dephosphorylation provides a mechanism for differential regulation of sodium channels by neurotrophins and tyrosine phosphorylation in unmyelinated axons and dendrites, where Na_V1.2 channels are expressed in brain neurons.

Key words: sodium channel; tyrosine; phosphorylation; modulation; Fyn; kinase

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Received Nov. 17, 2006; revised May 24, 2007; accepted July 10, 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

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