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.
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