title: Stochastic model of endothelial TRPV4 calcium sparklets: effect of bursting and cooperativity on EDH.
abstract: We examined the endothelial transient receptor vanilloid 4 (TRPV4) channel's vasodilatory signaling using mathematical modeling. The model analyzes experimental data by Sonkusare and coworkers on TRPV4-induced endothelial Ca(2+) events (sparklets). A previously developed continuum model of an endothelial and a smooth muscle cell coupled through microprojections was extended to account for the activity of a TRPV4 channel cluster. Different stochastic descriptions for the TRPV4 channel flux were examined using finite-state Markov chains. The model also took into consideration recent evidence for the colocalization of intermediate-conductance calcium-activated potassium channels (IKCa) and TRPV4 channels near the microprojections. A single TRPV4 channel opening resulted in a stochastic localized Ca(2+) increase in a small region (i.e., few μm(2) area) close to the channel. We predict micromolar Ca(2+) increases lasting for the open duration of the channel sufficient for the activation of low-affinity endothelial KCa channels. Simulations of a cluster of four TRPV4 channels incorporating burst and cooperative gating kinetics provided quantal Ca(2+) increases (i.e., steps of fixed amplitude), similar to the experimentally observed Ca(2+) sparklets. These localized Ca(2+) events result in endothelium-derived hyperpolarization (and SMC relaxation), with magnitude that depends on event frequency. The gating characteristics (bursting, cooperativity) of the TRPV4 cluster enhance Ca(2+) spread and the distance of KCa channel activation. This may amplify the EDH response by the additional recruitment of distant KCa channels.
authors: Department of Biomedical Engineering, Florida International University, Miami, Florida.
authors: Jaimit
authors: J
authors: Parikh
authors: Department of Biomedical Engineering, Florida International University, Miami, Florida.
authors: Adam
authors: A
authors: Kapela
authors: Department of Biomedical Engineering, Florida International University, Miami, Florida; School of Chemical Engineering, National Technical University of Athens, Athens, Greece. Electronic address: tsoukias@fiu.edu.
authors: Nikolaos M
authors: NM
authors: Tsoukias
mesh_terms: D002118:Calcium / Q000378:metabolism; D003198:Computer Simulation; D042783:Endothelial Cells / Q000378:metabolism; D007700:Kinetics; D008390:Markov Chains; D008958:Models, Molecular; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism; D013269:Stochastic Processes; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: D024681:Potassium Channels, Calcium-Activated; D050916:TRPV Cation Channels; D002118:Calcium