Store-independent modulation of Ca2+ entry through Orai by Septin 7

Orai channels are required for store-operated Ca²⁺ entry (SOCE) in multiple cell types. Septins are a class of GTP-binding proteins that function as diffusion barriers in cells. Here we show that Septin 7 acts as a `molecular brake' on activation of Orai channels in Drosophila neurons. Lowering Septin 7 levels results in dOrai-mediated Ca²⁺ entry and higher cytosolic Ca²⁺ in resting neurons. This Ca²⁺ entry is independent of depletion of endoplasmic reticulum Ca²⁺ stores and Ca²⁺ release through the inositol-1,4,5-trisphosphate receptor. Importantly, store-independent Ca²⁺ entry through Orai compensates for reduced SOCE in the Drosophila flight circuit. Moreover, overexpression of Septin 7 reduces both SOCE and flight duration, supporting its role as a negative regulator of Orai channel function in vivo. Septin 7 levels in neurons can, therefore, alter neural circuit function by modulating Orai function and Ca²⁺ homeostasis.