Endoplasmic Reticulum Remodeling Tunes IP(3)-Dependent Ca(2+) Release Sensitivity

The activation of vertebrate development at fertilization relies on IP(3)-dependent Ca(2+) release, a pathway that is sensitized during oocyte maturation. This sensitization has been shown to correlate with the remodeling of the endoplasmic reticulum into large ER patches, however the mechanisms involved are not clear. Here we show that IP(3) receptors within ER patches have a higher sensitivity to IP(3) than those in the neighboring reticular ER. The lateral diffusion rate of IP(3) receptors in both ER domains is similar, and ER patches dynamically fuse with reticular ER, arguing that IP(3) receptors exchange freely between the two ER compartments. These results suggest that increasing the density of IP(3) receptors through ER remodeling is sufficient to sensitize IP(3)-dependent Ca(2+) release. Mathematical modeling supports this concept of ‘geometric sensitization’ of IP(3) receptors as a population, and argues that it depends on enhanced Ca(2+)-dependent cooperativity at sub-threshold IP(3) concentrations. This represents a novel mechanism of tuning the sensitivity of IP(3) receptors through ER remodeling during meiosis.