Differential regulation of ER Ca2+ uptake and release rates accounts for multiple modes of Ca2+-induced Ca2+ release

The ER is a central element in Ca2+ signaling, both as a modulator Of cytoplasmic Ca2+ concentration ([Ca2+](i)) and as a locus of Ca2+-regulated events. During surface Membrane depolarization in excitable cells, the ER may either accumulate or release net Ca2+. but the conditions Of Stimulation that determine which form Of net Ca2+ transport Occurs are not well Understood. The direction of net ER Ca2+ transport depends oil the relative rates Of Ca2+ uptake and release via distinct pathways that are differentially regulated by Ca2+, so we investigated these rates and their sensitivity, to Ca2+ using sympathetic neurons as model cells. The rate of Ca2+ uptake by SERCAs (J(SERCA)), measured as the t-BuBHQ-sensitive component of the total cytoplasmic Ca2+ flux, increased monotonically with [Ca2+](i). Measurement of the rate of Ca2+ release (J(Release)) during t-BuBHQ-induced [Ca2+](i) transients made it possible to characterize the Ca2+ permeability of the ER (P-ER), describing the activity of all Ca2+-permeable channels that contribute to passive ER Ca2+ release, including ryanodine-sensitive Ca2+ release channels (RvRs) that are responsible for CICR. Simulations based oil experimentally determined descriptions of J(SERCA). PER, and of Ca2+ extrusion across the plasma membrane (J(pm)) accounted for our previous finding that during weal, depolarization, the ER accumulates Ca2+. but at a rate that is attenuated by activation of a CICR pathway operating in parallel with SERCAs to regulate net ER Ca2+ transport. Caffeine greatly increased the [Ca2+] sensitivity Of PER, accounting for the effects of caffeine on depolarization-evoked [Ca2+](i) elevations and caffeine-induced [Ca2+](i), oscillations. Extending the rate descriptions of J(SERCA), PER, and J(pm) to higher [Ca2+](i) levels shows how the interplay between Ca2+ transport systems with different Ca2+ sensitivities accounts for the different modes of CICR over different ranges of [Ca2+](i) during stimulation.