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 on 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 (⁠