HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 1, 418-428, January 6, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/1/418    most recent M510980200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Soldovieri, M. V. Articles by Taglialatela, M. Search for Related Content PubMed PubMed Citation Articles by Soldovieri, M. V. Articles by Taglialatela, M. Social Bookmarking                      What's this?

Decreased Subunit Stability as a Novel Mechanism for Potassium Current Impairment by a KCNQ2 C Terminus Mutation Causing Benign Familial Neonatal Convulsions^*

Maria Virginia Soldovieri1, Pasqualina Castaldo1, Luisa Iodice¶, Francesco Miceli, Vincenzo Barrese, Giulia Bellini||**, Emanuele Miraglia del Giudice**, Antonio Pascotto||, Stefano Bonatti¶, Lucio Annunziato, and Maurizio Taglialatela2

From the Division of Pharmacology, Department of Neuroscience, and ^¶Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, 80131 Naples, the ^||Chair of Child Neuropsychiatry and ^**Department of Pediatrics, Second University of Naples, 80131 Naples, the Department of Neuroscience, University of Ancona, 60121 Ancona, and the Department of Health Sciences, University of Molise, 86100 Campobasso, Italy

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 (2043T) 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 2043T 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 2043T 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.

Received for publication, October 7, 2005

^* This work was supported by European Union Specific Targeted Research Project (Grant PL 503038), the Italian National Institute of Health (Ministero della Salute) (Grants RF/2002, RF/2003, and RC/2002), the Italian Ministry of the University and Research (Grants FIRB RBNE01XMP4 and RBNE01E7YX_007), the Telethon (Project GGP030209), the Regione Campania Regional Law 5 of 28/3/2002 (year 2003), and the Centro Regionale di Competenza per il Trasferimento Tecnologico Industriale della Genomica Strutturale e Funzionale degli Organismi Superiori. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 39-0874-404856; Fax: 39-0874-404778; E-mail: mtaglial{at}unina.it.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. Etxeberria, P. Aivar, J. A. Rodriguez-Alfaro, A. Alaimo, P. Villace, J. C. Gomez-Posada, P. Areso, and A. Villarroel Calmodulin regulates the trafficking of KCNQ2 potassium channels FASEB J, April 1, 2008; 22(4): 1135 - 1143. [Abstract] [Full Text] [PDF]

				S. Maljevic, T. V. Wuttke, and H. Lerche Nervous system KV7 disorders: breakdown of a subthreshold brake J. Physiol., April 1, 2008; 586(7): 1791 - 1801. [Abstract] [Full Text] [PDF]

				M. V. Soldovieri, M. R. Cilio, F. Miceli, G. Bellini, E. Miraglia del Giudice, P. Castaldo, C. C. Hernandez, M. S. Shapiro, A. Pascotto, L. Annunziato, et al. Atypical Gating Of M-Type Potassium Channels Conferred by Mutations in Uncharged Residues in the S4 Region of KCNQ2 Causing Benign Familial Neonatal Convulsions J. Neurosci., May 2, 2007; 27(18): 4919 - 4928. [Abstract] [Full Text] [PDF]