Atypical gating of M-type potassium channels conferred by mutations in uncharged residues in the S4 region of KCNQ2 causing benign familial neonatal convulsions

Maria Virginia Soldovieri, Maria Roberta Cilio, Francesco Miceli, Giulia Bellini, Emanuele Miraglia Del Giudice, Pasqualina Castaldo, Ciria C. Hernandez, Mark S. Shapiro, Antonio Pascotto, Lucio Annunziato, Maurizio Taglialatela

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Heteromeric assembly of KCNQ2 and KCNQ3 subunits underlie the M-current (IKM), a slowly activating and noninactivating neuronal K+ current. Mutations in KCNQ2 and KCNQ3 genes cause benign familial neonatal convulsions (BFNCs), a rare autosomal-dominant epilepsy of the newborn. In the present study, we describe the identification of a novel KCNQ2 heterozygous mutation (c587t) in a BFNC-affected family, leading to an alanine to valine substitution at amino acid position 196 located at the N-terminal end of the voltage-sensing S4 domain. The consequences on KCNQ2 subunit function prompted by the A196V substitution, as well as by the A196V/L197P mutation previously described in another BFNC-affected family, were investigated by macroscopic and single-channel current measurements in CHO cells transiently transfected with wild-type and mutant subunits. When compared with KCNQ2 channels, homomeric KCNQ2 A196V or A196V/L197P channels showed a 20 mV rightward shift in their activation voltage dependence, with no concomitant change in maximal open probability or single-channel conductance. Furthermore, current activation kinetics of KCNQ2 A196V channels displayed an unusual dependence on the conditioning prepulse voltage, being markedly slower when preceded by prepulses to more depolarized potentials. Heteromeric channels formed by KCNQ2 A196V and KCNQ3 subunits displayed gating changes similar to those of KCNQ2 A196V homomeric channels. Collectively, these results reveal a novel role for noncharged residues in the N-terminal end of S4 in controlling gating of IKM and suggest that gating changes caused by mutations at these residues may decrease IKM function, thus causing neuronal hyperexcitability, ultimately leading to neonatal convulsions.

Original languageEnglish (US)
Pages (from-to)4919-4928
Number of pages10
JournalJournal of Neuroscience
Volume27
Issue number18
DOIs
StatePublished - May 2 2007

Keywords

  • Benign familial neonatal convulsions
  • Channel gating
  • Epilepsy
  • KCNQ2 subunits
  • Mutations
  • Potassium channels

ASJC Scopus subject areas

  • Neuroscience(all)

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