Figure 5. Model of Ca²⁺ tunnelling.

Cartoon depicting the mechanism of Ca²⁺ tunnelling downstream of Ca²⁺ store depletion and SOCE activation. Two distinct separate microdomains are at play. The SOCE microdomain, defined by STIM1‐Orai1 interactions, mediates Ca²⁺ flow from the extracellular space into the narrow ER–PM junction where it is taken up into the ER through the action of SERCA. The second domain is defined by IP₃R release sites that localize close to CaCCs to selectively activate them. Ca²⁺ flows from the extracellular space through Orai1 resulting in a localized Ca²⁺ microdomain that is spatially limited due to rapid uptake of Ca²⁺ by SERCA into the ER lumen. With open IP₃Rs, Ca²⁺ flowing into the ER leaks out through IP₃R to activate CaCC.