title: Novel HCN2 mutation contributes to febrile seizures by shifting the channel's kinetics in a temperature-dependent manner.
abstract: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel-mediated currents, known as I h, are involved in the control of rhythmic activity in neuronal circuits and in determining neuronal properties including the resting membrane potential. Recent studies have shown that HCN channels play a role in seizure susceptibility and in absence and limbic epilepsy including temporal lobe epilepsy following long febrile seizures (FS). This study focused on the potential contributions of abnormalities in the HCN2 isoform and their role in FS. A novel heterozygous missense mutation in HCN2 exon 1 leading to p.S126L was identified in two unrelated patients with FS. The mutation was inherited from the mother who had suffered from FS in a pedigree. To determine the effect of this substitution we conducted whole-cell patch clamp electrophysiology. We found that mutant channels had elevated sensitivity to temperature. More specifically, they displayed faster kinetics at higher temperature. Kinetic shift by change of temperature sensitivity rather than the shift of voltage dependence led to increased availability of I h in conditions promoting FS. Responses to cyclic AMP did not differ between wildtype and mutant channels. Thus, mutant HCN2 channels cause significant cAMP-independent enhanced availability of I h during high temperatures, which may contribute to hyperthermia-induced neuronal hyperexcitability in some individuals with FS.
authors: Department of Pediatrics, Faculty of Medicine, Fukuoka University, Fukuoka, Japan ; The Research Institute for the Molecular Pathomechanisms of Epilepsy, Fukuoka University, Fukuoka, Japan.
authors: Yuki
authors: Y
authors: Nakamura
authors: Xiuyu
authors: X
authors: Shi
authors: Tomohiro
authors: T
authors: Numata
authors: Yasuo
authors: Y
authors: Mori
authors: Ryuji
authors: R
authors: Inoue
authors: Christoph
authors: C
authors: Lossin
authors: Tallie Z
authors: TZ
authors: Baram
authors: Shinichi
authors: S
authors: Hirose
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016022:Case-Control Studies; D002648:Child; D000242:Cyclic AMP / Q000378:metabolism; D005091:Exons; D057809:HEK293 Cells; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000235:genetics* / Q000378:metabolism; D007700:Kinetics; D008564:Membrane Potentials; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D018408:Patch-Clamp Techniques; D010375:Pedigree; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D003294:Seizures, Febrile / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013696:Temperature
chemical_list: C578710:HCN2 protein, human; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015221:Potassium Channels; D000242:Cyclic AMP