Premium
A Mathematical Model of Calcium and cAMP Signaling in Pulmonary Microvascular Endothelial Cells
Author(s) -
Webb Kristal J,
Wiles C Alex,
Annamdevula Naga,
Sweat Rachel,
Britain Andrea L,
Phan AnhVu,
Townsley Mary I,
Leavesley Silas J,
Rich Thomas C
Publication year - 2016
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.30.1_supplement.969.26
Subject(s) - agonist , intracellular , phosphodiesterase , cytosol , chemistry , biophysics , compartment (ship) , calcium in biology , calcium , microbiology and biotechnology , receptor , biology , biochemistry , enzyme , oceanography , organic chemistry , geology
The goal of this project is to understand how the spatial distribution of intracellular Ca 2+ alters the kinetics and spatial spread of agonist‐induced cAMP signals in pulmonary microvascular endothelial cells (PMVECs). PMVECs predominantly contain the Ca 2+ ‐inhibited adenylyl cyclase type 6 (AC6) and also contain low levels of the Ca 2+ ‐stimulated phosphodiesterase type 1 (PDE1). It has been clearly demonstrated that Ca 2+ influx through store operated Ca 2+ (SOC) channels inhibits AC6 activity in PMVECs. Our preliminary data indicate that Ca 2+ influx through T‐type Ca 2+ channels and TRPV4 cation channels inhibits agonist‐induced cAMP production. We have developed mathematical models to investigate how the spatial reach of Ca 2+ influx through each of these channels alters agonist‐induced cAMP signals. The models describing this intracellular feedback network were developed in the MATLAB programming environment. Our initial models used ordinary differential equations to describe the kinetics and spatial redistribution of Ca 2+ and cAMP signals between intracellular compartments. Based upon experimental observations, Ca 2+ channels were distributed in three discrete subplasmalemmal compartments. In addition, a fourth cytosolic compartment was incorporated into the model. This model also describes Ca 2+ and cAMP buffering as well as Ca 2+ efflux. A Runge‐Kutta solver was used to perform numerical integration. Simulations of the model predict that at low agonist levels, low levels of Ca 2+ influx, Ca 2+ signals do not readily spread between compartments. Similarly, the model predicts that agonist‐induced cAMP signals do not readily spread between compartments. Thus, Ca 2+ influx in one compartment leads to localized inhibition of AC6 and a localized decrease in cAMP. We conclude that at low agonist concentrations, activation of different populations of Ca 2+ channels regulates different pools of AC6 thus cAMP levels in different subcellular compartments. However, at higher and/or prolonged agonist concentrations, Ca 2+ signals spread between intracellular compartments, increasing the range of AC6 inhibition. We are currently extending this model to more accurately describe the relative diffusion of second messengers using a finite element analysis approach. Support or Funding Information This work was supported by NIH P01HL066299 and T32HL076125.