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Mechanisms underlying cAMP compartmentation
Author(s) -
Feinstein Wei,
Britain Andrea L,
Rich Thomas C
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.887.3
Subject(s) - phosphodiesterase , nucleus , diffusion , biophysics , chemistry , microbiology and biotechnology , physics , biology , enzyme , biochemistry , thermodynamics
There is mounting evidence suggesting that specificity within cAMP signaling pathways is caused by compartmentation. Mechanisms underlying compartmentation are poorly understood. The spatial spread of cAMP is affected by phosphodiesterase (PDE) localization, buffering, cell geometry, and restrictions on diffusion. We developed mathematical models to investigate potential contributions of these mechanisms in the compartmentation of cAMP. Models assumed realistic enzyme concentrations and homogenous rates of diffusion. Initial simulations used an effective diffusion coefficient ( D ) of 300 μm 2 /s ‐ D for cAMP in aqueous solution. Simulations of cAMP spread within a spherical cell indicated that PDE activity and buffering by PKA cannot solely account for the segregation of cAMP signals, regardless of their subcellular location. When D was lowered 10,000‐fold, significant cAMP gradients were observed. We then incorporated realistic geometries of endothelial cells into the mathematical model. In simulations of this model with D = 300 μm 2 /s and PDE activity concentrated at the nuclear membrane, 3‐fold cAMP gradients were observed between cellular processes and the nucleus. Lowering D 100‐fold increased the magnitude of cAMP gradients. These simulations are consistent with a conceptual model in which cell geometry and structural elements contribute to cAMP compartmentation.