SEPT7-mediated regulation of Ca²⁺ entry through Orai channels requires other septin subunits

Orai channels are plasma membrane resident Ca²⁺ channels that allow extracellular Ca²⁺ uptake after depletion of ER-Ca²⁺ stores by a process called store-operated Ca²⁺ entry (SOCE). Septins of the SEPT2 subgroup act as positive regulators of SOCE in human nonexcitable cells. SEPT2 subgroup septins form the central core of hetero-hexameric or hetero-octameric complexes with SEPT6, SEPT7 and SEPT9 subgroup septins. The presence of fewer septin encoding genes coupled with ease of genetic manipulation allows for better understanding of septin subgroup function in Drosophila. Our earlier findings show that although dSEPT7 reduction does not alter Orai-mediated Ca²⁺ entry during SOCE, it results in constitutive activation of Orai channels in resting neurons. Here, we have investigated the role of other septin subgroup members in regulating Orai channel activation in Drosophila neurons by both cellular and functional assays. We show that dSEPT1, a SEPT2 subgroup septin can exist in a complex with dSEPT2 and dSEPT7 in the central nervous system (CNS) of Drosophila. Our findings suggest that the nature of septin filaments and heteromers obtained after reducing septins of different subgroups alters their ability to regulate Orai channel opening. The molecular mechanisms underlying this complex regulation of Orai function by septins require further cellular investigations.