Fig. 1. Schematic of the core Ca²⁺ regulatory system.

PM Ca²⁺ pump PMCA maintains a large gradient of Ca²⁺ across the PM. Ca²⁺ pump SERCA in the ER membrane fills an ER Ca²⁺ store that is used in rapid signaling events. Both pump proteins maintain these gradients against the effects of leak through regulated and constitutively active Ca²⁺ channels. Depletion of the ER Ca²⁺ store triggers influx of Ca²⁺ from the outside in a process termed SOC, which is inhibited by ER Ca²⁺. Our experimental approach combined thapsigargin (TG) to block SERCA with EGTA to chelate external Ca²⁺, thus blocking entry of Ca²⁺ from the outside. Dashed arrows indicate passive, but possibly regulated, leak. Solid arrows indicate ATP (adenosine 5′-triphosphate)–driven pump activities. Numbers in white circles reference model terms in Fig. 2D.