title: 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.
abstract: 1,4,5-trisphosphate (IP(3))-dependent Ca(2+) signaling regulates gonad function, fertility, and rhythmic posterior body wall muscle contraction (pBoc) required for defecation in Caenorhabditis elegans. Store-operated Ca(2+) entry (SOCE) is activated during endoplasmic reticulum (ER) Ca(2+) store depletion and is believed to be an essential and ubiquitous component of Ca(2+) signaling pathways. SOCE is thought to function to refill Ca(2+) stores and modulate Ca(2+) signals. Recently, stromal interaction molecule 1 (STIM1) was identified as a putative ER Ca(2+) sensor that regulates SOCE. We cloned a full-length C. elegans stim-1 cDNA that encodes a 530-amino acid protein with approximately 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-1GFP expression, suppresses the EF-hand mutation-induced pBoc arrhythmia, and inhibits intestinal store-operated Ca(2+) (SOC) channels. However, stim-1 RNAi surprisingly has no effect on pBoc rhythm, which is controlled by intestinal oscillatory Ca(2+) signaling, in wild type and IP(3) signaling mutant worms, and has no effect on intestinal Ca(2+) oscillations and waves. Depletion of intestinal Ca(2+) stores by RNAi knockdown of the ER Ca(2+) 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 Ca(2+) signaling processes and for maintenance of store Ca(2+) levels in C. elegans. These findings raise interesting and important questions regarding the function of SOCE and SOC channels under normal and pathophysiological conditions.
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Yan
authors.forename: Juan
authors.initials: J
authors.lastname: Xing
authors.forename: Catherine
authors.initials: C
authors.lastname: Lorin-Nebel
authors.forename: Ana Y
authors.initials: AY
authors.lastname: Estevez
authors.forename: Keith
authors.initials: K
authors.lastname: Nehrke
authors.forename: Todd
authors.initials: T
authors.lastname: Lamitina
authors.forename: Kevin
authors.initials: K
authors.lastname: Strange
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology*; D003001:Cloning, Molecular; D003672:Defecation / Q000235:genetics / Q000502:physiology; D004594:Electrophysiology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005260:Female; D005298:Fertility / Q000235:genetics / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism; D008565:Membrane Proteins / Q000502:physiology*; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000235:genetics / Q000502:physiology; D009154:Mutation / Q000235:genetics; D010060:Ovulation / Q000235:genetics / Q000502:physiology; D034622:RNA Interference / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D000071737:Stromal Interaction Molecule 1
chemical_list: D029742:Caenorhabditis elegans Proteins; D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008565:Membrane Proteins; D000071737:Stromal Interaction Molecule 1; C516629:stim-1 protein, C elegans; D002118:Calcium