title: Oscillation of cAMP and Ca(2+) in cardiac myocytes: a systems biology approach.
abstract: Cyclic adenosine monophosphate (cAMP) and Ca(2+) levels may oscillate in harmony within excitable cells; a mathematical oscillation loop model, the Cooper model, of these oscillations was developed two decades ago. However, in that model all adenylyl cyclase (AC) isoforms were assumed to be inhibited by Ca(2+), and it is now known that the heart expresses multiple AC isoforms, among which the type 5/6 isoforms are Ca(2+)-inhibitable whereas the other five (AC2, 3, 4, 7, and 9) are not. We used a computational systems biology approach with CellDesigner simulation software to develop a comprehensive graphical map and oscillation loop model for cAMP and Ca(2+). This model indicated that Ca(2+)-mediated inhibition of AC is essential to create oscillations of Ca(2+) and cAMP, and the oscillations were not altered by incorporation of phosphodiesterase-mediated cAMP hydrolysis or PKA-mediated inhibition of AC into the model. More importantly, they were created but faded out immediately in the co-presence of Ca(2+)-noninhibitable AC isoforms. Because the subcellular locations of AC isoforms are different, spontaneous cAMP and Ca(2+) oscillations may occur within microdomains containing only Ca(2+)-inhibitable isoforms in cardiac myocytes, which might be necessary for fine tuning of excitation-contraction coupling.
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
authors.forename: Takehisa
authors.initials: T
authors.lastname: Kamide
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okumura
authors.forename: Samik
authors.initials: S
authors.lastname: Ghosh
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shinoda
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Mototani
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Ohnuki
authors.forename: Huiling
authors.initials: H
authors.lastname: Jin
authors.forename: Wenqian
authors.initials: W
authors.lastname: Cai
authors.forename: Kenji
authors.initials: K
authors.lastname: Suita
authors.forename: Itaru
authors.initials: I
authors.lastname: Sato
authors.forename: Masanari
authors.initials: M
authors.lastname: Umemura
authors.forename: Takayuki
authors.initials: T
authors.lastname: Fujita
authors.forename: Utako
authors.initials: U
authors.lastname: Yokoyama
authors.forename: Motohiko
authors.initials: M
authors.lastname: Sato
authors.forename: Kazuharu
authors.initials: K
authors.lastname: Furutani
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kitano
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ishikawa
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D019295:Computational Biology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D056966:Excitation Contraction Coupling / Q000502:physiology; D006868:Hydrolysis; D008962:Models, Theoretical; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D012984:Software; D049490:Systems Biology
chemical_list: D020033:Protein Isoforms; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D010727:Phosphoric Diester Hydrolases; D000262:Adenylyl Cyclases; D002118:Calcium