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

Nat Commun. 2015 Mar 27:6:6488. doi: 10.1038/ncomms7488.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Animals
  • Cell Membrane / metabolism*
  • Chromatography, Gel
  • Circular Dichroism
  • Drosophila
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Entropy
  • Gene Expression Regulation, Developmental*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Magnetic Resonance Spectroscopy
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Post-Synaptic Density / metabolism*
  • Protein Binding
  • RNA, Messenger / metabolism*
  • Shaker Superfamily of Potassium Channels / genetics
  • Shaker Superfamily of Potassium Channels / metabolism*
  • Surface Plasmon Resonance
  • Tumor Suppressor Proteins

Substances

  • Drosophila Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • RNA, Messenger
  • Shaker Superfamily of Potassium Channels
  • Tumor Suppressor Proteins
  • dlg1 protein, Drosophila