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¹ Department of Anesthesiology, Department of Molecular Physiology and Biophysics, and Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232
² Department of Medicine, Division of Nephrology, University of Rochester Medical Center, Rochester, NY 14642

Correspondence to Kevin Strange: kevin.strange{at}vanderbilt.edu

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.

T. Lamitina's present address is Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104.

Abbreviations used in this paper: CV, coefficient of variance; DIC, differential interference contrast; FRET, fluorescence resonance energy transfer; I_CRAC, Ca²⁺ release–activated Ca²⁺ current; IP₃, 1,4,5-trisphosphate; IP₃R, IP₃ receptor; SCID, severe combined immunodeficiency; SERCA, sarcoplasmic/ER Ca²⁺ ATPase; SOCE, store-operated Ca²⁺ entry; STIM1, stromal interaction molecule 1; UPR, unfolded protein response.

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