Key result
Alternative splicing of the Shaker Kv channel gene produces variants of distinct tail lengths that modulate channel clustering and cell surface expression through an entropic 'ball and chain' mechanism.
The length of the intrinsically disordered C-terminal tail of the Shaker Kv channel acts as an entropic clock, modulating its binding affinity to PSD-95 and subsequent channel clustering via a 'ball and chain' mechanism.
No immediate clinical implications; leaves open translation of tail-length mechanisms to human Kv channelopathies.
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. Ion channel clustering at specific membrane sites plays a fundamental role in action potential transmission. Here, the authors show that alternative splice variants of the intrinsically disordered C-terminal segment of the Shaker Kv channel support distinct patterns of scaffold protein-mediated channel clustering.
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Zandany et al. (2015) studied this question. Alternative splicing of Shaker Kv channel C-terminal tail vs. Different length tail variants (ShA vs ShB) was evaluated on Kv channel clustering metrics and PSD-95 binding affinity. Alternative splicing of the Shaker Kv channel gene produces variants of distinct tail lengths that modulate channel clustering and cell surface expression through an entropic 'ball and chain' mechanism.
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