Polarized axonal surface expression of neuronal KCNQ channels is mediated by multiple signals in the KCNQ2 and KCNQ3 C-terminal domains

Proc Natl Acad Sci U S A. 2006 Jun 6;103(23):8870-5. doi: 10.1073/pnas.0603376103. Epub 2006 May 30.


The M channels, important regulators of neuronal excitability, are voltage-gated potassium channels composed of KCNQ2-5 subunits. Mutations in KCNQ2 and KCNQ3 cause benign familial neonatal convulsions (BFNC), dominantly inherited epilepsy and myokymia. Crucial for their functions in controlling neuronal excitability, the M channels must be placed at specific regions of the neuronal membrane. However, the precise distribution of surface KCNQ channels is not known. Here, we show that KCNQ2/KCNQ3 channels are preferentially localized to the surface of axons both at the axonal initial segment and more distally. Whereas axonal initial segment targeting of surface KCNQ channels is mediated by ankyrin-G binding motifs of KCNQ2 and KCNQ3, sequences mediating targeting to more distal portion of the axon reside in the membrane proximal and A domains of the KCNQ2 C-terminal tail. We further show that several BFNC mutations of KCNQ2 and KCNQ3 disrupt surface expression or polarized surface distribution of KCNQ channels, thereby revealing impaired targeting of KCNQ channels to axonal surfaces as a BFNC etiology.

Publication types

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

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Ankyrins / metabolism
  • Axons / metabolism*
  • Cell Polarity*
  • Epilepsy, Benign Neonatal / genetics
  • Gene Expression*
  • KCNQ2 Potassium Channel / chemistry*
  • KCNQ2 Potassium Channel / metabolism*
  • KCNQ3 Potassium Channel / chemistry*
  • KCNQ3 Potassium Channel / metabolism*
  • Mutation / genetics
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein Transport
  • Rats
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction


  • Ankyrins
  • KCNQ2 Potassium Channel
  • KCNQ3 Potassium Channel
  • Recombinant Fusion Proteins