期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 103, 期 34, 页码 12923-12928出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0600137103
关键词
fluorescence imaging; models; signal transduction
资金
- NCRR NIH HHS [RR08605, P41 RR008605] Funding Source: Medline
- NHLBI NIH HHS [P01 HL046345, HL46345] Funding Source: Medline
- NIDDK NIH HHS [R01 DK073368, DK73368] Funding Source: Medline
- NIGMS NIH HHS [P20 GM072033, GM72033] Funding Source: Medline
- NINDS NIH HHS [R37 NS027177, NS27177, R01 NS027177] Funding Source: Medline
Compartmentation and dynamics of cAMP and PKA signaling are important determinants of specificity among cAMP's myriad cellular roles. Both cardiac inotropy and the progression of heart disease are affected by spatiotemporal variations in cAMP/PKA signaling, yet the dynamic patterns of PKA-mediated phosphorylation that influence differential responses to agonists have not been characterized. We performed live-cell imaging and systems modeling of PKA-mediated phosphorylation in neonatal cardiac myocytes in response to G-protein coupled receptor stimuli and UV photolysis of caged cAMP. cAMP accumulation was rate-limiting in PKA-mediated phosphorylation downstream of the beta-adrenergic receptor. Prostaglandin El stimulated higher PKA activity in the cytosol than at the sarcolemma, whereas isoproterenol triggered faster sarcolemmal responses than cytosolic, likely due to restricted cAMP diffusion from submembrane compartments. Localized UV photolysis of caged cAMP triggered gradients of PKA-mediated phosphorylation, enhanced by phosphodiesterase activity and PKA-mediated buffering of cAMP. These findings indicate that combining live-cell FRET imaging and mechanistic computational models can provide quantitative understanding of spatiotemporal signaling.
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