A computational analysis of localized Ca2+-dynamics generated by heterogeneous release sites

We investigate the role of heterogeneous expression of IP3R and RyR in generating diverse elementary Ca2+ signals. It has been shown empirically (Wojcikiewicz and Luo in Mol. Pharmacol. 53(4):656-662, 1998; Newton et al. in J. Biol. Chem. 269(46):28613-28619, 1994; Smedt et al. in Biochem. J. 322(Pt. 2):575-583, 1997) that tissues express various proportions of IP3 and RyR isoforms and this expression is dynamically regulated (Parrington et al. in Dev. Biol. 203(2):451-461, 1998; Fissore et al. in Biol. Reprod. 60(1):49-57, 1999; Tovey et al. in J. Cell Sci. 114(Pt. 22):3979-3989, 2001). Although many previous theoretical studies have investigated the dynamics of localized calcium release sites (Swillens et al. in Proc. Natl. Acad. Sci. U.S.A. 96(24):13750-13755, 1999; Shuai and Jung in Proc. Natl. Acad. Sci. U.S.A. 100(2):506-510, 2003a; Shuai and Jung in Phys. Rev. E, Stat. Nonlinear Soft Matter Phys. 67(3 Pt. 1):031905, 2003b; Thul and Falcke in Biophys. J. 86(5):2660-2673, 2004; DeRemigio and Smith in Cell Calcium 38(2):73-86, 2005; Nguyen et al. in Bull. Math. Biol. 67(3):393-432, 2005), so far all such studies focused on release sites consisting of identical channel types. We have extended an existing mathematical model (Nguyen et al. in Bull. Math. Biol. 67(3):393-432, 2005) to release sites with two (or more) receptor types, each with its distinct channel kinetics. Mathematically, the release site is represented by a transition probability matrix for a collection of nonidentical stochastically gating channels coupled through a shared Ca2+ domain. We demonstrate that under certain conditions a previously defined mean-field approximation of the coupling strength does not accurately reproduce the release site dynamics. We develop a novel approximation and establish that its performance in these instances is superior. We use this mathematical framework to study the effect of heterogeneity in the Ca2+-regulation of two colocalized channel types on the release site dynamics. We consider release sites consisting of channels with both Ca2+-activation and inactivation ("four-state channels") and channels with Ca2+-activation only ("two-state channels") and show that for the appropriate parameter values, synchronous channel openings within a release site with any proportion of two-state to four-state channels are possible, however, the larger the proportion of two-state channels, the more sensitive the dynamics are to the exact spatial positioning of the channels and the distance between channels. Specifically, the clustering of even a small number of two-state channels interferes with puff/spark termination and increases puff durations or leads to a tonic response.