Oscillation of cAMP and Ca2+ in cardiac myocytes: a systems biology approach
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Cyclic adenosine monophosphate (cAMP) and Ca2+ 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 Ca2+, and it is now known that the heart expresses multiple AC isoforms, among which the type 5/6 isoforms are Ca2+-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 Ca2+. This model indicated that Ca2+-mediated inhibition of AC is essential to create oscillations of Ca2+ 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 Ca2+-noninhibitable AC isoforms. Because the subcellular locations of AC isoforms are different, spontaneous cAMP and Ca2+ oscillations may occur within microdomains containing only Ca2+-inhibitable isoforms in cardiac myocytes, which might be necessary for fine tuning of excitation–contraction coupling.
KeywordsAdenlyl cyclase Subtype Computational analysis Oscillation Cyclic AMP Calcium
This study was supported in part by grants from the Ministry of Health, Labor, and Welfare (Dr Ishikawa), a Grant-in-Aid for Scientific Research on Innovative Areas (22136009), and Grants from the Japanese Ministry of Education, Culture, Sports, Science, and Technology (Drs Ishikawa, Okumura, Fujita, Sato, Yokoyama, Mototani), the National Cerebral and Cardiovascular Center (Dr Ishikawa), the Takeda Science Foundation (Dr Okumura), the Yokohama Foundation for Advancement of Medical Science (Dr Okumura), the Yokohama Academic Foundation (Dr Ohnuki), the Research Foundation for Community Medicine (Dr Okumura), and the Suzuken Memorial Foundation (Dr Okumura).
Conflict of interest
The authors declare no potential conflicts of interest.
- 2.Okumura S, Kawabe J, Yatani A, Takagi G, Lee MC, Hong C, Liu J, Takagi I, Sadoshima J, Vatner DE, Vatner SF, Ishikawa Y (2003) Type 5 adenylyl cyclase disruption alters not only sympathetic but also parasympathetic and calcium-mediated cardiac regulation. Circ Res 93:364–371CrossRefPubMedGoogle Scholar
- 3.Okumura S, Fujita T, Cai W, Jin M, Namekata I, Mototani Y, Jin H, Ohnuki Y, Tsuneoka Y, Bai Y, Suzuki S, Hidaka Y, Umemura M, Ichikawa Y, Yokoyama U, Sato M, Ishikawa F, Izumi-Nakaseko H, Adachi-Akahane S, Tanaka H, Ishikawa Y (2014) EPAC1-dependent phospholamban phosphorylation mediates the cardiac response to stresses. J Clin Invest 124:2785–2801CrossRefPubMedCentralPubMedGoogle Scholar
- 9.Okumura S, Vatner DE, Kurotani R, Bai Y, Gao S, Yuan Z, Iwatsubo K, Ulucan C, Kawabe J, Gjosh K, Vatner SF, Ishikawa Y (2007) Disruption of type 5 adenylyl cyclase enhances desensitization of cyclic adenosine monophosphate signal and increases Akt signal with chronic catecholamine stress. Circulation 116:1776–1783CrossRefPubMedGoogle Scholar
- 10.Ohnuki Y, Umeki D, Mototani Y, Jin H, Cai W, Shiozawa K, Suita K, Saeki Y, Fujita T, Ishikawa Y, Okumura S (2014) Role of cyclic AMP sensor epac1 in masseter muscle hypertrophy and myosin heavy chain transition induced by β2-adrenoceptor stimulation. J Physiol 592:5461–5475CrossRefPubMedGoogle Scholar
- 14.Katsushika S, Chen L, Kawabe J, Nilakantan R, Halnon NJ, Homcy C, Ishikawa Y (1992) Cloning and characterization of a sixth adenylyl cyclase isoform: types V and VI constitute a subgroup within the mammalian adenylyl cyclase family. Proc Natl Acad Sci USA 89:8774–8778CrossRefPubMedCentralPubMedGoogle Scholar
- 16.Timofeyev V, Myers RE, Kim HJ, Woltz RL, Sirish P, Heiserman JP, Li N, Singapuri A, Tang T, Yarov-Yarovoy V, Yamoah EN, Hammond HK, Chiamvimonvat N (2013) Adenylyl cyclase subtype-specific compartmentalization: differential regulation of L-type Ca2+ current in ventricular myocytes. Circ Res 112:1567–1576CrossRefPubMedCentralPubMedGoogle Scholar
- 18.Espinasse I, Iourgenko V, Defer N, Samson F, Hanoune J, Mercadier JJ (1995) Type V, but not type VI, adenylyl cyclase mRNA accumulates in the rat heart during ontogenic development. Correlation with increased global adenylyl cyclase activity. J Mol Cell Cardiol 27:1789–1795CrossRefPubMedGoogle Scholar
- 32.Masaki N, Fujimoto K, Honda-Kitahara M, Hada E, Sawai S (2013) Robustness of self-organizing chemoattractant field arising from precise pulse induction of its breakdown enzyme: a single-cell level analysis of PDE expression in Dictyostelium. Biophys J 104:1191–1202CrossRefPubMedCentralPubMedGoogle Scholar
- 33.Okumura S, Tsunematsu T, Bai Y, Jiao Q, Ono S, Suzuki S, Kurotani R, Sato M, Minamisawa S, Umemura S, Ishikawa Y (2008) Type 5 adenylyl cyclase plays a major role in stabilizing heart rate in response to microgravity induced by parabolic flight. J Appl Physiol 1985 105:173–179CrossRefPubMedCentralPubMedGoogle Scholar
- 34.Bai Y, Tsunematsu T, Jiao Q, Ohnuki Y, Mototani Y, Shiozawa K, Jin M, Cai W, Jin HL, Fujita T, Ichikawa Y, Suita K, Kurotani R, Yokoyama U, Sato M, Iwatsubo K, Isikawa Y (2012) Pharmacological stimulation of type 5 adenylyl cyclase stabilizes heart rate under both microgravity and hypergravity induced by parabolic flight. J Pharmacol Sci 119:381–389CrossRefPubMedGoogle Scholar