Syntaxin-binding domain of Kv2.1 is essential for the expression of apoptotic K+ currents

J Physiol. 2014 Aug 15;592(16):3511-21. doi: 10.1113/jphysiol.2014.276964. Epub 2014 Jun 13.


Intracellular signalling cascades triggered by oxidative injury can lead to upregulation of Kv2.1 K(+) channels at the plasma membrane of dying neurons. Membrane incorporation of new channels is necessary for enhanced K(+) efflux and a consequent reduction of intracellular K(+) that facilitates apoptosis. We showed previously that the observed increase in K(+) currents is a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-mediated process, and that the SNARE protein syntaxin binds directly to Kv2.1 channels. In the present study, we tested whether disrupting the interaction of Kv2.1 and syntaxin promoted the survival of cortical neurons following injury. Syntaxin is known to bind to Kv2.1 in a domain comprising amino acids 411-522 of the channel's cytoplasmic C terminus (C1a). Here we show that this domain is required for the apoptotic K(+) current enhancement. Moreover, expression of an isolated, Kv2.1-derived C1a peptide is sufficient to suppress the injury-induced increase in currents by interfering with Kv2.1/syntaxin binding. By subdividing the C1a peptide, we were able to localize the syntaxin binding site on Kv2.1 to the most plasma membrane-distal residues of C1a. Importantly, expression of this peptide segment in neurons prevented the apoptotic K(+) current enhancement and cell death following an oxidative insult, without greatly impairing baseline K(+) currents or normal electrical profiles of neurons. These results establish that binding of syntaxin to Kv2.1 is crucial for the manifestation of oxidant-induced apoptosis, and thereby reveal a potential new direction for therapeutic intervention in the treatment of neurodegenerative disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials*
  • Animals
  • Apoptosis*
  • Binding Sites
  • CHO Cells
  • Cells, Cultured
  • Cricetinae
  • Cricetulus
  • Female
  • Male
  • Potassium / metabolism
  • Protein Binding
  • Qa-SNARE Proteins / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Shab Potassium Channels / chemistry
  • Shab Potassium Channels / metabolism*


  • Qa-SNARE Proteins
  • Shab Potassium Channels
  • Potassium