Function of a STIM1 Homologue in C. elegans: Evidence that Store-operated Ca²⁺ Entry Is Not Essential for Oscillatory Ca²⁺ Signaling and ER Ca²⁺ Homeostasis

1,4,5-trisphosphate (IP₃)-dependent Ca²⁺ signaling regulates gonad function, fertility, and rhythmic posterior body wall muscle contraction (pBoc) required for defecation in Caenorhabditis elegans. Store-operated Ca²⁺ entry (SOCE) is activated during endoplasmic reticulum (ER) Ca²⁺ store depletion and is believed to be an essential and ubiquitous component of Ca²⁺ signaling pathways. SOCE is thought to function to refill Ca²⁺ stores and modulate Ca²⁺ signals. Recently, stromal interaction molecule 1 (STIM1) was identified as a putative ER Ca²⁺ sensor that regulates SOCE. We cloned a full-length C. elegans stim-1 cDNA that encodes a 530–amino acid protein with ∼21% sequence identity to human STIM1. Green fluorescent protein (GFP)–tagged STIM-1 is expressed in the intestine, gonad sheath cells, and spermatheca. Knockdown of stim-1 expression by RNA interference (RNAi) causes sterility due to loss of sheath cell and spermatheca contractile activity required for ovulation. Transgenic worms expressing a STIM-1 EF-hand mutant that constitutively activates SOCE in Drosophila and mammalian cells are sterile and exhibit severe pBoc arrhythmia. stim-1 RNAi dramatically reduces STIM-1∷GFP expression, suppresses the EF-hand mutation–induced pBoc arrhythmia, and inhibits intestinal store-operated Ca²⁺ (SOC) channels. However, stim-1 RNAi surprisingly has no effect on pBoc rhythm, which is controlled by intestinal oscillatory Ca²⁺ signaling, in wild type and IP₃ signaling mutant worms, and has no effect on intestinal Ca²⁺ oscillations and waves. Depletion of intestinal Ca²⁺ stores by RNAi knockdown of the ER Ca²⁺ pump triggers the ER unfolded protein response (UPR). In contrast, stim-1 RNAi fails to induce the UPR. Our studies provide the first detailed characterization of STIM-1 function in an intact animal and suggest that SOCE is not essential for certain oscillatory Ca²⁺ signaling processes and for maintenance of store Ca²⁺ levels in C. elegans. These findings raise interesting and important questions regarding the function of SOCE and SOC channels under normal and pathophysiological conditions.