Orai channels are plasma membrane resident Ca channels that allow extracellular Ca uptake after depletion of ER-Ca stores by a process called store-operated Ca entry (SOCE). Septins of the SEPT2 subgroup act as positive regulators of SOCE in human non-excitable 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 Ca 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. This article is protected by copyright. All rights reserved.