Mathematical Biology seminar

Bori Mazzag
Math Dept., University of Utah
"The feedback of a localized calcium domain on calcium-gated channels"
September 29
3:05pm in LCB 215

Single channel models of intracellular Ca2+ channels such as the inositol 1,4,5-trisphosphate (Ip3) receptor and ryanodine receptor often assume that Ca2+-dependent transitions are mediated by a constant background [Ca2+] as opposed to a dynamic [Ca2+] representing the formation and collapse of a localized Ca2+ domain. This assumption neglects the fact that Ca2+ released by open intracellular Ca2+ channels may influence subsequent gating through the processes of Ca2+-activation or Ca2+-inactivation. We study the effect of such ``residual Ca2+'' from previous channel opening on the stochastic gating of minimal and realistic single channel models coupled to either a restricted cytoplasmic compartment or a spherically symmetric calcium domain. We show, using both Monte-Carlo simulations and analytical estimates, that the steady-state open probability (Po) of single channel models depends on the comparison between the time scales determined by the channel kinetics and the formation and collapse of Ca2+ domain. We show how these approaches can be generalized for arbitrarily complex channel models, for example the De Young-Keizer Ip3 receptor model. When the ordinary differential equation for the [Ca2+] in a restricted cytoplasmic compartment is replaced by a partial differential equation for the buffered diffusion of intracellular Ca2+ in a homogeneous isotropic cytosol, we find the dependence of Po on the buffer length constant is qualitatively similar to the above mentioned results, while the dependence of Po on the buffer time constant is reversed. We show preliminary results to illustrate that extensions of our current work to clusters of Ca2+-gated Ca2+ channels may lead to deeper understanding of synchronous channel activity thought to underlie emergent behavior such as calcium puffs.