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The Journal of Neuroscience, May 2, 2007, 27(18):4919-4928; doi:10.1523/JNEUROSCI.0580-07.2007

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Neurobiology of Disease
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,¹ Maria Roberta Cilio,² Francesco Miceli,¹ Giulia Bellini,³ Emanuele Miraglia del Giudice,⁴ Pasqualina Castaldo,¹ Ciria C. Hernandez,⁵ Mark S. Shapiro,⁵ Antonio Pascotto,³ Lucio Annunziato,¹ and Maurizio Taglialatela^1,6

¹Section of Pharmacology, Department of Neuroscience, University of Naples Federico II, 80131 Naples, Italy, ²Division of Neurology, Bambino Gesù Children's Hospital, 00165 Rome, Italy, Departments of ³Child Neuropsychiatry, and ⁴Pediatrics, Second University of Naples, 80138 Naples, Italy, ⁵Department of Physiology, University of Texas Health Science Center, San Antonio, Texas 78229-3900, and ⁶Department of Health Science, University of Molise, 86100 Campobasso, Italy

Correspondence should be addressed to Dr. Maurizio Taglialatela, Division of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, Ed. 19, Via Pansini 5, 80131 Naples, Italy. Email: mtaglial{at}unina.it

Heteromeric assembly of KCNQ2 and KCNQ3 subunits underlie the M-current (I_KM), 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 I_KM and suggest that gating changes caused by mutations at these residues may decrease I_KM function, thus causing neuronal hyperexcitability, ultimately leading to neonatal convulsions.

Key words: epilepsy; potassium channels; KCNQ2 subunits; benign familial neonatal convulsions; channel gating; mutations

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Received Feb. 9, 2007; revised March 16, 2007; accepted April 4, 2007.

Correspondence should be addressed to Dr. Maurizio Taglialatela, Division of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, Ed. 19, Via Pansini 5, 80131 Naples, Italy. Email: mtaglial{at}unina.it

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