Alternative splicing modulates Kv channel clustering through a molecular ball and chain mechanism

Nitzan Zandany, Shir Marciano, Elhanan Magidovich, Teddy Frimerman, Rinat Yehezkel, Tzilhav Shem-Ad, Limor Lewin, Uri Abdu, Irit Orr and Ofer Yifrach ()
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Nitzan Zandany: Zlotowski Center for Neurosciences, Ben-Gurion University of the Negev
Shir Marciano: Zlotowski Center for Neurosciences, Ben-Gurion University of the Negev
Elhanan Magidovich: Zlotowski Center for Neurosciences, Ben-Gurion University of the Negev
Teddy Frimerman: Zlotowski Center for Neurosciences, Ben-Gurion University of the Negev
Rinat Yehezkel: Zlotowski Center for Neurosciences, Ben-Gurion University of the Negev
Tzilhav Shem-Ad: Zlotowski Center for Neurosciences, Ben-Gurion University of the Negev
Limor Lewin: Zlotowski Center for Neurosciences, Ben-Gurion University of the Negev
Uri Abdu: Zlotowski Center for Neurosciences, Ben-Gurion University of the Negev
Irit Orr: Zlotowski Center for Neurosciences, Ben-Gurion University of the Negev
Ofer Yifrach: Zlotowski Center for Neurosciences, Ben-Gurion University of the Negev

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: Abstract Ion channel clustering at the post-synaptic density serves a fundamental role in action potential generation and transmission. Here, we show that interaction between the Shaker Kv channel and the PSD-95 scaffold protein underlying channel clustering is modulated by the length of the intrinsically disordered C terminal channel tail. We further show that this tail functions as an entropic clock that times PSD-95 binding. We thus propose a ‘ball and chain’ mechanism to explain Kv channel binding to scaffold proteins, analogous to the mechanism describing channel fast inactivation. The physiological relevance of this mechanism is demonstrated in that alternative splicing of the Shaker channel gene to produce variants of distinct tail lengths resulted in differential channel cell surface expression levels and clustering metrics that correlate with differences in affinity of the variants for PSD-95. We suggest that modulating channel clustering by specific spatial-temporal spliced variant targeting serves a fundamental role in nervous system development and tuning.

Date: 2015
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DOI: 10.1038/ncomms7488

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