Modeling local and global intracellular calcium responses mediated by diffusely distributed inositol 1,4,5-trisphosphate receptors

J Theor Biol. 2008 Jul 7;253(1):170-88. doi: 10.1016/j.jtbi.2008.02.040. Epub 2008 Mar 6.

Abstract

Considerable insight into intracellular Ca2+ responses has been obtained through the development of whole cell models that are based on molecular mechanisms, e.g., single channel kinetics of the inositol 1,4,5-trisphosphate (IP3) receptor Ca2+ channel. However, a limitation of most whole cell models to date is the assumption that IP3 receptor Ca2+ channels (IP3Rs) are globally coupled by a "continuously stirred" bulk cytosolic [Ca2+], when in fact open IP3Rs experience elevated "domain" Ca2+ concentrations. Here we present a 2N+2-compartment whole cell model of local and global Ca2+ responses mediated by N=100,000 diffusely distributed IP3Rs, each represented by a four-state Markov chain. Two of these compartments correspond to bulk cytosolic and luminal Ca2+ concentrations, and the remaining 2N compartments represent time-dependent cytosolic and luminal Ca2+ domains associated with each IP3R. Using this Monte Carlo model as a starting point, we present an alternative formulation that solves a system of advection-reaction equations for the probability density of cytosolic and luminal domain [Ca2+] jointly distributed with IP3R state. When these equations are coupled to ordinary differential equations for the bulk cytosolic and luminal [Ca2+], a realistic but minimal model of whole cell Ca2+ dynamics is produced that accounts for the influence of local Ca2+ signaling on channel gating and global Ca2+ responses. The probability density approach is benchmarked and validated by comparison to Monte Carlo simulations, and the two methods are shown to agree when the number of Ca2+ channels is large (i.e., physiologically realistic). Using the probability density approach, we show that the time scale of Ca2+ domain formation and collapse (both cytosolic and luminal) may influence global Ca2+ oscillations, and we derive two reduced models of global Ca2+ dynamics that account for the influence of local Ca2+ signaling on global Ca2+ dynamics when there is a separation of time scales between the stochastic gating of IP3Rs and the dynamics of domain Ca2+.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium Channels / metabolism
  • Calcium Signaling*
  • Computer Simulation*
  • Cytosol / metabolism*
  • Inositol 1,4,5-Trisphosphate / metabolism
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism*
  • Ion Channel Gating
  • Markov Chains
  • Models, Biological
  • Models, Chemical*
  • Monte Carlo Method

Substances

  • Calcium Channels
  • Inositol 1,4,5-Trisphosphate Receptors
  • Inositol 1,4,5-Trisphosphate
  • Calcium