Decreased subunit stability as a novel mechanism for potassium current impairment by a KCNQ2 C terminus mutation causing benign familial neonatal convulsions

J Biol Chem. 2006 Jan 6;281(1):418-28. doi: 10.1074/jbc.M510980200. Epub 2005 Oct 31.


KCNQ2 and KCNQ3 K+ channel subunits underlie the muscarinic-regulated K+ current (I(KM)), a widespread regulator of neuronal excitability. Mutations in KCNQ2- or KCNQ3-encoding genes cause benign familiar neonatal convulsions (BFNCs), a rare autosomal-dominant idiopathic epilepsy of the newborn. In the present study, we have investigated, by means of electrophysiological, biochemical, and immunocytochemical techniques in transiently transfected cells, the consequences prompted by a BFNC-causing 1-bp deletion (2043deltaT) in the KCNQ2 gene; this frameshift mutation caused the substitution of the last 163 amino acids of the KCNQ2 C terminus and the extension of the subunit by additional 56 residues. The 2043deltaT mutation abolished voltage-gated K+ currents produced upon homomeric expression of KCNQ2 subunits, dramatically reduced the steady-state cellular levels of KCNQ2 subunits, and prevented their delivery to the plasma membrane. Metabolic labeling experiments revealed that mutant KCNQ2 subunits underwent faster degradation; 10-h treatment with the proteasomal inhibitor MG132 (20 microm) at least partially reversed such enhanced degradation. Co-expression with KCNQ3 subunits reduced the degradation rate of mutant KCNQ2 subunits and led to their expression on the plasma membrane. Finally, co-expression of KCNQ2 2043deltaT together with KCNQ3 subunits generated functional voltage-gated K+ currents having pharmacological and biophysical properties of heteromeric channels. Collectively, the present results suggest that mutation-induced reduced stability of KCNQ2 subunits may cause epilepsy in neonates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Carcinoma, Hepatocellular
  • Cell Line, Tumor
  • Cell Membrane / physiology
  • Cricetinae
  • Epilepsy, Benign Neonatal / genetics*
  • Epilepsy, Benign Neonatal / physiopathology
  • Frameshift Mutation
  • Green Fluorescent Proteins / genetics
  • Humans
  • Infant, Newborn
  • KCNQ2 Potassium Channel / chemistry
  • KCNQ2 Potassium Channel / genetics*
  • KCNQ2 Potassium Channel / physiology*
  • KCNQ3 Potassium Channel / chemistry
  • KCNQ3 Potassium Channel / genetics
  • KCNQ3 Potassium Channel / physiology
  • Liver Neoplasms
  • Mutagenesis
  • Patch-Clamp Techniques
  • Protein Subunits / chemistry
  • Protein Subunits / physiology*
  • Transfection


  • KCNQ2 Potassium Channel
  • KCNQ3 Potassium Channel
  • Protein Subunits
  • Green Fluorescent Proteins