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

Maria Virginia Soldovieri, Pasqualina Castaldo, Luisa Iodice, Francesco Miceli, Vincenzo Barrese, Giulia Bellini, Emanuele Miraglia Del Giudice, Antonio Pascotto, Stefano Bonatti, Lucio Annunziato, Maurizio Taglialatela

Research output: Contribution to journalArticlepeer-review

Abstract

KCNQ2 and KCNQ3 K+ channel subunits underlie the muscarinic-regulated K+ current (IKM), 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 (2043ΔT) 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 2043ΔT 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 μM) 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 2043ΔT 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.

Original languageEnglish
Pages (from-to)418-428
Number of pages11
JournalJournal of Biological Chemistry
Volume281
Issue number1
DOIs
Publication statusPublished - Jan 6 2006

ASJC Scopus subject areas

  • Biochemistry

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