title: Systems modeling of Ca(2+) homeostasis and mobilization in platelets mediated by IP3 and store-operated Ca(2+) entry.
abstract: Resting platelets maintain a stable level of low cytoplasmic calcium ([Ca(2+)]cyt) and high dense tubular system calcium ([Ca(2+)]dts). During thrombosis, activators cause a transient rise in inositol trisphosphate (IP3) to trigger calcium mobilization from stores and elevation of [Ca(2+)]cyt. Another major source of [Ca(2+)]cyt elevation is store-operated calcium entry (SOCE) through plasmalemmal calcium channels that open in response to store depletion as [Ca(2+)]dts drops. A 34-species systems model employed kinetics describing IP3-receptor, DTS-plasmalemma puncta formation, SOCE via assembly of STIM1 and Orai1, and the plasmalemma and sarco/endoplasmic reticulum Ca(2+)-ATPases. Four constraints were imposed: calcium homeostasis before activation; stable in zero extracellular calcium; IP3-activatable; and functional SOCE. Using a Monte Carlo method to sample three unknown parameters and nine initial concentrations in a 12-dimensional space near measured or expected values, we found that model configurations that were responsive to stimuli and demonstrated significant SOCE required high inner membrane electric potential (>-70 mV) and low resting IP3 concentrations. The absence of puncta in resting cells was required to prevent spontaneous store depletion in calcium-free media. Ten-fold increases in IP3 caused saturated calcium mobilization. This systems model represents a critical step in being able to predict platelets' phenotypes during hemostasis or thrombosis.
authors.affiliation: Institute for Medicine and Engineering, Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Dolan
authors.affiliation: Institute for Medicine and Engineering, Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: sld@seas.upenn.edu.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Diamond
mesh_terms: D001692:Biological Transport; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D016000:Cluster Analysis; D005110:Extracellular Space / Q000378:metabolism; D006706:Homeostasis; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000819:agonists / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism*; D008954:Models, Biological
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D007295:Inositol Phosphates; D002118:Calcium