Endoplasmic Reticulum Remodeling Tunes IP3-Dependent Ca2+ Release Sensitivity

Abstract

The activation of vertebrate development at fertilization relies on IP3-dependent Ca2+ 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 IP3 receptors within ER patches have a higher sensitivity to IP3 than those in the neighboring reticular ER. The lateral diffusion rate of IP3 receptors in both ER domains is similar, and ER patches dynamically fuse with reticular ER, arguing that IP3 receptors exchange freely between the two ER compartments. These results suggest that increasing the density of IP3 receptors through ER remodeling is sufficient to sensitize IP3-dependent Ca2+ release. Mathematical modeling supports this concept of ‘geometric sensitization’ of IP3 receptors as a population, and argues that it depends on enhanced Ca2+-dependent cooperativity at sub-threshold IP3 concentrations. This represents a novel mechanism of tuning the sensitivity of IP3 receptors through ER remodeling during meiosis.

The Role of IP3 Receptor Channel Clustering in Ca2+ Wave Propagation During Oocyte Maturation

“…These numbers are approximately consistent with reports in Ref. 22 and 23. PMCA and SOCE are present, while PLC d is not.…”

“…The model starts on the organizational scale of calcium release through clusters of IP 3 Rs and takes into account calcium extrusion through PMCAs (plasma membrane calcium ATPases), Ca 2þ sequestration through SERCA (sarco-endoplasmic reticulum calcium ATPases), Ca 2þ influx through SOCE, and calcium-induced IP 3 production through PLC d to predict cellular calcium dynamics. It allows us to test the effects of changes in PMCA, SOCE, and spatial distributions of the release channels, that is, mimicking ER remodeling as reported in by Terasaki et al 9 and Sun et al, 22 for calcium signals on the cellular scale. The goal is to use the experimental observations (changes in wave speed, signal duration, sensitivity to stimulation by IP 3 , and spatial reorganization) in conjunction with the computational model to extract the most critical determinants of calcium-signaling differentiation during oocyte maturation.…”

“…2,3 Indeed, we have recently shown that ER remodeling contributes significantly to sensitizing IP 3 -dependent Ca 2þ release during oocyte maturation. 22 While all these changes have been established, their relative contributions to the mode of propagation of the Ca 2þ release wave during oocyte maturation remain unclear. Given the complexity and close interaction of Ca 2þ signaling pathways, it is difficult to address the contribution of individual pathways in isolation in the physiologic context.…”

Mid-range Ca2+ signalling mediated by functional coupling between store-operated Ca2+ entry and IP3-dependent Ca2+ release

“…The constructs for mCh-STIM1, YFP-STIM1, Orai1-GFP, GFP-IP3R and TMEM16a-mCh have been previously described 45,47,64 . The GFPtagged SERCA2b was a generous gift from James Lechleiter.…”

Egg activation in physiologically polyspermic newt eggs: involvement of IP3 receptor, PLCγ, and microtubules in calcium wave induction

“…In hippocampal neurons, large ER vesicles that are capable of taking up and releasing Ca 2+ move along the dendrite microtubules, probably by a motor protein of kinesin (Bannai et al, 2004;Mikoshiba, 2007). It is also known that the remodeling of the ER into large ER patches gives IP 3 receptors within the ER patches higher sensitivity to IP 3 in mature Xenopus oocytes (Sun et al, 2011). Thus, microtubules in the newt eggs seem be necessary for ER-clustering to promote the propagative Ca 2+ release for the Ca 2+ wave.…”