Sites and molecular mechanisms of modulation of Na(v)1.2 channels by Fyn tyrosine kinase.

Sites and molecular mechanisms of modulation of Na(v)1.2 channels by Fyn tyrosine kinase. Research Abstract Details 

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Sites and molecular mechanisms of modulation of Na(v)1.2 channels by Fyn tyrosine kinase. Abstract Text:

Daniel Beacham,Misol Ahn,William A Catterall,Todd Scheuer,

Voltage-gated sodium channels are important targets for modulation of electrical excitability by neurotransmitters and neurotrophins acting through protein phosphorylation. Fast inactivation of Na(V)1.2 channels is regulated via tyrosine phosphorylation by Fyn kinase and dephosphorylation by receptor phosphoprotein tyrosine phosphatase-beta, which are associated in a signaling complex. Here we have identified the amino acid residues on Na(V)1.2 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(V)1.2, 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(V)1.1 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(V)1.2 channels are expressed in brain neurons.

Sites and molecular mechanisms of modulation of Na(v)1.2 channels by Fyn tyrosine kinase. Publishing Authors By Initials

D Beacham,M Ahn,WA Catterall,T Scheuer,

For similar proteins: carrier proteins: membrane transport proteins: ion channels: sodium channels research abstracts see: proteins: carrier proteins: membrane transport proteins: ion channels: sodium channels research

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MEDLINE DATE:

Sites and molecular mechanisms of modulation of Na(v)1.2 channels by Fyn tyrosine kinase. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: The Journal of neuroscience : the official journal

VOLUME: 27

Page Numbers: 11543-51

Journal Abbreviation: J. Neurosci.

ISSN: 1529-2401

DAY: 24

MONTH: Oct

YEAR: 2007

Sites and molecular mechanisms of modulation of Na(v)1.2 channels by Fyn tyrosine kinase. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 8102140

Sites and molecular mechanisms of modulation of Na(v)1.2 channels by Fyn tyrosine kinase. Keywords Mesh Terms:

KEYWORDS: Sodium Channels

MESH TERMS: metabolism

Chemical & Substance for Abstract: Sites and molecular mechanisms of modulation of Na(v)1.2 channels by Fyn tyrosine kinase. Information

Substance Name: Proto-Oncogene Proteins c-fyn

Registry Number: EC 2.7.1.112

Grant and Affiliation Information for Sites and molecular mechanisms of modulation of Na(v)1.2 channels by Fyn tyrosine kinase.

AFFILIATION: Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280, USA.

Country: United States

AGENCY: United States NINDS

GRANT: NS25704

ACRONYM: NS

MEDLINETA: J Neurosci

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