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Kv3.3 Potassium Channels Activate the TBK1 Signaling Pathway

26 Pages Posted: 10 Jul 2018 Sneak Peek Status: Review Complete

See all articles by Yalan Zhang

Yalan Zhang

Yale University - Department of Pharmacology

Louis Varela

Yale University - Department of Comparative Medicine

Klara Szigeti-Buck

Yale University - Department of Comparative Medicine

Jorge Henao-Mejia

Yale University - Department of Immunobiology

Richard A. Flavell

Yale University - Department of Immunobiology

Tamas L. Horvath

Yale University - Department of Comparative Medicine

Leonard K. Kaczmarek

Yale University - Department of Pharmacology

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Abstract

Mutations in KCNC3, which encodes the Kv3.3 potassium channel, are linked to degeneration of the cerebellum (SCA13, spinocerebellar ataxia type 13). We found that Kv3.3 channels bind and stimulate Tank Binding Kinase 1 (TBK1), an enzyme that controls trafficking of membrane proteins into multivesicular bodies. TBK1 activity regulates binding of the channel with Hax-1, an anti-apoptotic protein required for survival of cerebellar neurons, and that embeds Kv3.3 in a stable actin cytoskeleton at the plasma membrane. TBK1 activity is elevated several-fold in the cerebellum of animals expressing a SCA13 mutant channel. Cells that express the mutant channel have increased internalization of Hax-1 and accumulate multivesicular bodies containing this cell survival protein, coupled to depolarization-induced loss of the channels themselves. Our studies indicate that the activation of Kv3.3 channels is linked directly to TBK1 activity and channel mutations enhance internalization of the cell survival protein Hax-1 to which they are bound.

Suggested Citation

Zhang, Yalan and Varela, Louis and Szigeti-Buck, Klara and Henao-Mejia, Jorge and Flavell, Richard A. and Horvath, Tamas L. and Kaczmarek, Leonard K., Kv3.3 Potassium Channels Activate the TBK1 Signaling Pathway (2018). Available at SSRN: https://ssrn.com/abstract=3209877 or http://dx.doi.org/10.2139/ssrn.3209877
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Yalan Zhang

Yale University - Department of Pharmacology

New Haven, CT 06520
United States

Louis Varela

Yale University - Department of Comparative Medicine

New Haven, CT 06520
United States

Klara Szigeti-Buck

Yale University - Department of Comparative Medicine

New Haven, CT 06520
United States

Jorge Henao-Mejia

Yale University - Department of Immunobiology

300 Cedar Street
New Haven, CT 06520
United States

Richard A. Flavell

Yale University - Department of Immunobiology

300 Cedar Street
New Haven, CT 06520
United States

Tamas L. Horvath

Yale University - Department of Comparative Medicine

New Haven, CT 06520
United States

Leonard K. Kaczmarek (Contact Author)

Yale University - Department of Pharmacology ( email )

New Haven, CT 06520
United States

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