title: CaMKII modulates sodium current in neurons from epilepticScn2amutant mice.
abstract: Monogenic epilepsies with wide-ranging clinical severity have been associated with mutations in voltage-gated sodium channel genes. In theScn2aQ54mouse model of epilepsy, a focal epilepsy phenotype is caused by transgenic expression of an engineered NaV1.2 mutation displaying enhanced persistent sodium current. Seizure frequency and other phenotypic features inScn2aQ54mice depend on genetic background. We investigated the neurophysiological and molecular correlates of strain-dependent epilepsy severity in this model.Scn2aQ54mice on the C57BL/6J background (B6.Q54) exhibit a mild disorder, whereas animals intercrossed with SJL/J mice (F1.Q54) have a severe phenotype. Whole-cell recording revealed that hippocampal pyramidal neurons from B6.Q54 and F1.Q54 animals exhibit spontaneous action potentials, but F1.Q54 neurons exhibited higher firing frequency and greater evoked activity compared with B6.Q54 neurons. These findings correlated with larger persistent sodium current and depolarized inactivation in neurons from F1.Q54 animals. Because calcium/calmodulin protein kinase II (CaMKII) is known to modify persistent current and channel inactivation in the heart, we investigated CaMKII as a plausible modulator of neuronal sodium channels. CaMKII activity in hippocampal protein lysates exhibited a strain-dependence inScn2aQ54mice with higher activity in F1.Q54 animals. Heterologously expressed NaV1.2 channels exposed to activated CaMKII had enhanced persistent current and depolarized channel inactivation resembling the properties of F1.Q54 neuronal sodium channels. By contrast, inhibition of CaMKII attenuated persistent current, evoked a hyperpolarized channel inactivation, and suppressed neuronal excitability. We conclude that CaMKII-mediated modulation of neuronal sodium current impacts neuronal excitability inScn2aQ54mice and may represent a therapeutic target for the treatment of epilepsy.
authors.affiliation: Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611 christopher.thompson1@northwestern.edu.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Thompson
authors.affiliation: Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Hawkins
authors.affiliation: Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kearney
authors.affiliation: Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D004827:Epilepsy / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008564:Membrane Potentials; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009154:Mutation; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D018408:Patch-Clamp Techniques; D012964:Sodium / Q000378:metabolism
chemical_list: D062551:NAV1.2 Voltage-Gated Sodium Channel; D012964:Sodium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: CaMKII; epilepsy; voltage-gated sodium channel