title: Calmodulin and calcium differentially regulate the neuronal Nav1.1 voltage-dependent sodium channel.
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(++) 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(++) could bind the Nav1.1 C-terminal region with micromolar affinity.
authors: INSERM U641, Institut Jean Roche, Marseille F-13344, France.
authors: Christelle
authors: C
authors: Gaudioso
authors: Edmond
authors: E
authors: Carlier
authors: Fahamoe
authors: F
authors: Youssouf
authors: Jeffrey J
authors: JJ
authors: Clare
authors: Dominique
authors: D
authors: Debanne
authors: Gisèle
authors: G
authors: Alcaraz
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D051381:Rats; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D020798:Two-Hybrid System Techniques
chemical_list: D002147:Calmodulin; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; C568250:Scn1a protein, rat; D015222:Sodium Channels; D002118:Calcium