title: Conservation of Ca2+/calmodulin regulation across Na and Ca2+ channels.
abstract: Voltage-gated Na and Ca2+ channels comprise distinct ion channel superfamilies, yet the carboxy tails of these channels exhibit high homology, hinting at a long-shared and purposeful module. For different Ca2+ channels, carboxyl-tail interactions with calmodulin do elaborate robust and similar forms of Ca2+ regulation. However, Na channels have only shown subtler Ca2+ modulation that differs among reports, challenging attempts at unified understanding. Here, by rapid Ca2+ photorelease onto Na channels, we reset this view of Na channel regulation. For cardiac-muscle channels (NaV1.5), reported effects from which most mechanistic proposals derive, we observe no Ca2+ modulation. Conversely, for skeletal-muscle channels (NaV1.4), we uncover fast Ca2+ regulation eerily similar to that of Ca2+ channels. Channelopathic myotonia mutations halve NaV1.4 Ca2+ regulation, and transplanting the NaV1.4 carboxy tail onto Ca2+ channels recapitulates Ca2+ regulation. Thus, we argue for the persistence and physiological relevance of an ancient Ca2+ regulatory module across Na and Ca2+ channels.
authors.affiliation: Calcium Signals Laboratory, Departments of Biomedical Engineering and Neuroscience and Center for Cell Dynamics, The Johns Hopkins University School of Medicine, Ross Building, Room 713, 720 Rutland Avenue, Baltimore, MD 21205, USA.
authors.forename: Manu
authors.initials: M
authors.lastname: Ben-Johny
authors.affiliation: Calcium Signals Laboratory, Departments of Biomedical Engineering and Neuroscience and Center for Cell Dynamics, The Johns Hopkins University School of Medicine, Ross Building, Room 713, 720 Rutland Avenue, Baltimore, MD 21205, USA.
authors.forename: Philemon S
authors.initials: PS
authors.lastname: Yang
authors.affiliation: Calcium Signals Laboratory, Departments of Biomedical Engineering and Neuroscience and Center for Cell Dynamics, The Johns Hopkins University School of Medicine, Ross Building, Room 713, 720 Rutland Avenue, Baltimore, MD 21205, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Niu
authors.affiliation: Calcium Signals Laboratory, Departments of Biomedical Engineering and Neuroscience and Center for Cell Dynamics, The Johns Hopkins University School of Medicine, Ross Building, Room 713, 720 Rutland Avenue, Baltimore, MD 21205, USA.
authors.forename: Wanjun
authors.initials: W
authors.lastname: Yang
authors.affiliation: Calcium Signals Laboratory, Departments of Biomedical Engineering and Neuroscience and Center for Cell Dynamics, The Johns Hopkins University School of Medicine, Ross Building, Room 713, 720 Rutland Avenue, Baltimore, MD 21205, USA.
authors.forename: Rosy
authors.initials: R
authors.lastname: Joshi-Mukherjee
authors.affiliation: Calcium Signals Laboratory, Departments of Biomedical Engineering and Neuroscience and Center for Cell Dynamics, The Johns Hopkins University School of Medicine, Ross Building, Room 713, 720 Rutland Avenue, Baltimore, MD 21205, USA. Electronic address: dyue@jhmi.edu.
authors.forename: David T
authors.initials: DT
authors.lastname: Yue
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002147:Calmodulin / Q000737:chemistry* / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D032342:Muscle Cells / Q000378:metabolism; D032446:Myoblasts / Q000378:metabolism; D010802:Phylogeny; D051381:Rats; D016415:Sequence Alignment; D061566:Voltage-Gated Sodium Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D002147:Calmodulin; D061566:Voltage-Gated Sodium Channels; D002118:Calcium