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Title: Calmodulin and calcium differentially regulate the neuronal Nav1.1 voltage-dependent sodium channel

Abstract

Highlights: {yields} Both Ca{sup ++}-Calmodulin (CaM) and Ca{sup ++}-free CaM bind to the C-terminal region of Nav1.1. {yields} Ca{sup ++} and CaM have both opposite and convergent effects on I{sub Nav1.1}. {yields} Ca{sup ++}-CaM modulates I{sub Nav1.1} amplitude. {yields} CaM hyperpolarizes the voltage-dependence of activation, and increases the inactivation rate. {yields} Ca{sup ++} alone antagonizes CaM for both effects, and depolarizes the voltage-dependence of inactivation. -- Abstract: Mutations in the neuronal Nav1.1 voltage-gated sodium channel are responsible for mild to severe epileptic syndromes. The ubiquitous calcium sensor calmodulin (CaM) bound to rat brain Nav1.1 and to the human Nav1.1 channel expressed by a stably transfected HEK-293 cell line. The C-terminal region of the channel, as a fusion protein or in the yeast two-hybrid system, interacted with CaM via a consensus C-terminal motif, the IQ domain. Patch clamp experiments on HEK1.1 cells showed that CaM overexpression increased peak current in a calcium-dependent way. CaM had no effect on the voltage-dependence of fast inactivation, and accelerated the inactivation kinetics. Elevating Ca{sup ++} depolarized the voltage-dependence of fast inactivation and slowed down the fast inactivation kinetics, and for high concentrations this effect competed with the acceleration induced by CaM alone. Similarly, the depolarizingmore » action of calcium antagonized the hyperpolarizing shift of the voltage-dependence of activation due to CaM overexpression. Fluorescence spectroscopy measurements suggested that Ca{sup ++} could bind the Nav1.1 C-terminal region with micromolar affinity.« less

Authors:
; ;  [1];  [2];  [3];  [1];  [2];  [1];  [2]
  1. INSERM U641, Institut Jean Roche, Marseille F-13344 (France)
  2. (France)
  3. Eaton Pharma Consulting, Eaton Socon, Cambridgeshire PE19 8EF (United Kingdom)
Publication Date:
OSTI Identifier:
22207413
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 411; Journal Issue: 2; Other Information: Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BRAIN; CALCIUM; CALCIUM IONS; CALMODULIN; COMPUTER-AIDED MANUFACTURING; CONCENTRATION RATIO; FLUORESCENCE SPECTROSCOPY; INACTIVATION; MUTATIONS; RATS; SENSORS; SODIUM; YEASTS

Citation Formats

Gaudioso, Christelle, Carlier, Edmond, Youssouf, Fahamoe, Universite de la Mediterranee, Faculte de Medecine Secteur Nord, IFR 11, Marseille F-13344, Clare, Jeffrey J., Debanne, Dominique, Universite de la Mediterranee, Faculte de Medecine Secteur Nord, IFR 11, Marseille F-13344, Alcaraz, Gisele, E-mail: gisele.alcaraz@univmed.fr, and Universite de la Mediterranee, Faculte de Medecine Secteur Nord, IFR 11, Marseille F-13344. Calmodulin and calcium differentially regulate the neuronal Nav1.1 voltage-dependent sodium channel. United States: N. p., 2011. Web. doi:10.1016/J.BBRC.2011.06.142.
Gaudioso, Christelle, Carlier, Edmond, Youssouf, Fahamoe, Universite de la Mediterranee, Faculte de Medecine Secteur Nord, IFR 11, Marseille F-13344, Clare, Jeffrey J., Debanne, Dominique, Universite de la Mediterranee, Faculte de Medecine Secteur Nord, IFR 11, Marseille F-13344, Alcaraz, Gisele, E-mail: gisele.alcaraz@univmed.fr, & Universite de la Mediterranee, Faculte de Medecine Secteur Nord, IFR 11, Marseille F-13344. Calmodulin and calcium differentially regulate the neuronal Nav1.1 voltage-dependent sodium channel. United States. doi:10.1016/J.BBRC.2011.06.142.
Gaudioso, Christelle, Carlier, Edmond, Youssouf, Fahamoe, Universite de la Mediterranee, Faculte de Medecine Secteur Nord, IFR 11, Marseille F-13344, Clare, Jeffrey J., Debanne, Dominique, Universite de la Mediterranee, Faculte de Medecine Secteur Nord, IFR 11, Marseille F-13344, Alcaraz, Gisele, E-mail: gisele.alcaraz@univmed.fr, and Universite de la Mediterranee, Faculte de Medecine Secteur Nord, IFR 11, Marseille F-13344. Fri . "Calmodulin and calcium differentially regulate the neuronal Nav1.1 voltage-dependent sodium channel". United States. doi:10.1016/J.BBRC.2011.06.142.
@article{osti_22207413,
title = {Calmodulin and calcium differentially regulate the neuronal Nav1.1 voltage-dependent sodium channel},
author = {Gaudioso, Christelle and Carlier, Edmond and Youssouf, Fahamoe and Universite de la Mediterranee, Faculte de Medecine Secteur Nord, IFR 11, Marseille F-13344 and Clare, Jeffrey J. and Debanne, Dominique and Universite de la Mediterranee, Faculte de Medecine Secteur Nord, IFR 11, Marseille F-13344 and Alcaraz, Gisele, E-mail: gisele.alcaraz@univmed.fr and Universite de la Mediterranee, Faculte de Medecine Secteur Nord, IFR 11, Marseille F-13344},
abstractNote = {Highlights: {yields} Both Ca{sup ++}-Calmodulin (CaM) and Ca{sup ++}-free CaM bind to the C-terminal region of Nav1.1. {yields} Ca{sup ++} and CaM have both opposite and convergent effects on I{sub Nav1.1}. {yields} Ca{sup ++}-CaM modulates I{sub Nav1.1} amplitude. {yields} CaM hyperpolarizes the voltage-dependence of activation, and increases the inactivation rate. {yields} Ca{sup ++} alone antagonizes CaM for both effects, and depolarizes the voltage-dependence of inactivation. -- Abstract: Mutations in the neuronal Nav1.1 voltage-gated sodium channel are responsible for mild to severe epileptic syndromes. The ubiquitous calcium sensor calmodulin (CaM) bound to rat brain Nav1.1 and to the human Nav1.1 channel expressed by a stably transfected HEK-293 cell line. The C-terminal region of the channel, as a fusion protein or in the yeast two-hybrid system, interacted with CaM via a consensus C-terminal motif, the IQ domain. Patch clamp experiments on HEK1.1 cells showed that CaM overexpression increased peak current in a calcium-dependent way. CaM had no effect on the voltage-dependence of fast inactivation, and accelerated the inactivation kinetics. Elevating Ca{sup ++} depolarized the voltage-dependence of fast inactivation and slowed down the fast inactivation kinetics, and for high concentrations this effect competed with the acceleration induced by CaM alone. Similarly, the depolarizing action of calcium antagonized the hyperpolarizing shift of the voltage-dependence of activation due to CaM overexpression. Fluorescence spectroscopy measurements suggested that Ca{sup ++} could bind the Nav1.1 C-terminal region with micromolar affinity.},
doi = {10.1016/J.BBRC.2011.06.142},
journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 2,
volume = 411,
place = {United States},
year = {2011},
month = {7}
}