title: Involvement of Ca(2+)-Dependent Hyperpolarization in Sleep Duration in Mammals.
abstract: The detailed molecular mechanisms underlying the regulation of sleep duration in mammals are still elusive. To address this challenge, we constructed a simple computational model, which recapitulates the electrophysiological characteristics of the slow-wave sleep and awake states. Comprehensive bifurcation analysis predicted that a Ca(2+)-dependent hyperpolarization pathway may play a role in slow-wave sleep and hence in the regulation of sleep duration. To experimentally validate the prediction, we generate and analyze 21 KO mice. Here we found that impaired Ca(2+)-dependent K(+) channels (Kcnn2 and Kcnn3), voltage-gated Ca(2+) channels (Cacna1g and Cacna1h), or Ca(2+)/calmodulin-dependent kinases (Camk2a and Camk2b) decrease sleep duration, while impaired plasma membrane Ca(2+) ATPase (Atp2b3) increases sleep duration. Pharmacological intervention and whole-brain imaging validated that impaired NMDA receptors reduce sleep duration and directly increase the excitability of cells. Based on these results, we propose a hypothesis that a Ca(2+)-dependent hyperpolarization pathway underlies the regulation of sleep duration in mammals.
authors.affiliation: Department of Systems Pharmacology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Fumiya
authors.initials: F
authors.lastname: Tatsuki
authors.affiliation: Laboratory for Synthetic Biology, RIKEN Quantitative Biology Center, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Genshiro A
authors.initials: GA
authors.lastname: Sunagawa
authors.affiliation: Department of Systems Pharmacology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Shoi
authors.initials: S
authors.lastname: Shi
authors.affiliation: Department of Systems Pharmacology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Laboratory for Synthetic Biology, RIKEN Quantitative Biology Center, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Etsuo A
authors.initials: EA
authors.lastname: Susaki
authors.affiliation: Laboratory for Synthetic Biology, RIKEN Quantitative Biology Center, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Yukinaga
authors.affiliation: Laboratory for Synthetic Biology, RIKEN Quantitative Biology Center, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan; School of Electrical Engineering and Computer Science, Queensland University of Technology, GPO Box 2434, Brisbane QLD 4001, Australia.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Perrin
authors.affiliation: Laboratory for Mouse Genetic Engineering, RIKEN Quantitative Biology Center, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Sumiyama
authors.affiliation: Laboratory for Synthetic Biology, RIKEN Quantitative Biology Center, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Ukai-Tadenuma
authors.affiliation: Laboratory for Synthetic Biology, RIKEN Quantitative Biology Center, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fujishima
authors.affiliation: Department of Systems Pharmacology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Rei-ichiro
authors.initials: R
authors.lastname: Ohno
authors.affiliation: Department of Systems Pharmacology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tone
authors.affiliation: Department of Systems Pharmacology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Laboratory for Synthetic Biology, RIKEN Quantitative Biology Center, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Koji L
authors.initials: KL
authors.lastname: Ode
authors.affiliation: Laboratory for Synthetic Biology, RIKEN Quantitative Biology Center, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Department of Systems Pharmacology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Laboratory for Synthetic Biology, RIKEN Quantitative Biology Center, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan. Electronic address: uedah-tky@umin.ac.jp.
authors.forename: Hiroki R
authors.initials: HR
authors.lastname: Ueda
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020747:Calcium Channels, T-Type / Q000235:genetics; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D003198:Computer Simulation; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004569:Electroencephalography; D004576:Electromyography; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010622:Phencyclidine / Q000494:pharmacology; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012890:Sleep / Q000187:drug effects / Q000235:genetics*; D012895:Sleep, REM / Q000187:drug effects / Q000235:genetics; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000235:genetics; D013997:Time Factors
chemical_list: C498197:Cacna1g protein, mouse; C504883:Cacna1h protein, mouse; D020747:Calcium Channels, T-Type; D018691:Excitatory Amino Acid Antagonists; C496898:Kcnn2 protein, mouse; C496900:Kcnn3 protein, mouse; D016194:Receptors, N-Methyl-D-Aspartate; D051640:Small-Conductance Calcium-Activated Potassium Channels; D016291:Dizocilpine Maleate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517671:Camk2a protein, mouse; C517672:Camk2b protein, mouse; D053499:Plasma Membrane Calcium-Transporting ATPases; D010622:Phencyclidine; D002118:Calcium