In neurons, the endoplasmic reticulum (ER) modulates elevations of the cytosolic free Ca2+ concentration ([Ca2+] ) in response to extracellular stimulation by accumulating Ca2+ via the sarcoplasmic/endoplasmic reticulum Ca2+-ATPases (SERCAs) or by releasing Ca2+ via the ER Ca2+ channels. SERCA inhibitors are often used as a tool for investigating the contribution from ER Ca2+ transport to the [Ca2+] dynamics. The respective effects on Ca2+ responses in different neurons are characterized by a large diversity. However, the factors that determine this diversity have not been completely understood. Using a simple two-compartment model of the Ca2+ dynamics, we showed that changes in the density and relative contribution of ryanodine receptors and SERCA pumps, stimulation conditions, and dye concentration are sufficient to reproduce either smoothly graded, or non-linearly graded, or all-or-non ER Ca2+ release and many effects of SERCA inhibitors on the Ca2+ transients observed in different neurons. Here, we have redefined main modes of the net ER Ca2+ transport (net Ca2+ uptake, non-regenerative Ca2+ release, and regenerative Ca2+ release) and showed that these modes are completely determined by the interplay between Ca2+ fluxes and the Ca2+ buffering rate. Our simulations demonstrate that low-gain models of Ca2+-induced calcium release (CICR) do not require any counteracting termination mechanism for the release termination. The simulations also suggested that Ca2+ transients in some neurons may be modestly amplified by regenerative CICR, which is, nonetheless, graded and self-limiting due to CICR termination mechanisms, such as store depletion and/or Ca2+-dependent inactivation of ryanodine receptors. However, a spatially homogeneous model fails to reproduce both smoothly graded and high- gain CICR.
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Saftenku, E. Modes of Operation of the Endoplasmic Reticulum Ca2+ Transport Systems in Neurons: Insights from the Compartmental Models. Neurophysiology 54, 2–13 (2022). https://doi.org/10.1007/s11062-023-09930-6
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DOI: https://doi.org/10.1007/s11062-023-09930-6