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Role of the Inositol-1,4,5-trisphosphate Receptor and Phospholipases C ß and

Maria V. Espelt, Ana Y. Estevez, Xiaoyan Yin, and Kevin Strange

Department of Anesthesiology, Department of Molecular Physiology and Biophysics, and Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232

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

Defecation in the nematode Caenorhabditis elegans is a readily observable ultradian behavioral rhythm that occurs once every 45–50 s and is mediated in part by posterior body wall muscle contraction (pBoc). pBoc is not regulated by neural input but instead is likely controlled by rhythmic Ca²⁺ oscillations in the intestinal epithelium. We developed an isolated nematode intestine preparation that allows combined physiological, genetic, and molecular characterization of oscillatory Ca²⁺ signaling. Isolated intestines loaded with fluo-4 AM exhibit spontaneous rhythmic Ca²⁺ oscillations with a period of 50 s. Oscillations were only detected in the apical cell pole of the intestinal epithelium and occur as a posterior-to-anterior moving intercellular Ca²⁺ wave. Loss-of-function mutations in the inositol-1,4,5-trisphosphate (IP₃) receptor ITR-1 reduce pBoc and Ca²⁺ oscillation frequency and intercellular Ca²⁺ wave velocity. In contrast, gain-of-function mutations in the IP₃ binding and regulatory domains of ITR-1 have no effect on pBoc or Ca²⁺ oscillation frequency but dramatically increase the speed of the intercellular Ca²⁺ wave. Systemic RNA interference (RNAi) screening of the six C. elegans phospholipase C (PLC)–encoding genes demonstrated that pBoc and Ca²⁺ oscillations require the combined function of PLC- and PLC-ß homologues. Disruption of PLC- and PLC-ß activity by mutation or RNAi induced arrhythmia in pBoc and intestinal Ca²⁺ oscillations. The function of the two enzymes is additive. Epistasis analysis suggests that PLC- functions primarily to generate IP₃ that controls ITR-1 activity. In contrast, IP₃ generated by PLC-ß appears to play little or no direct role in ITR-1 regulation. PLC-ß may function instead to control PIP₂ levels and/or G protein signaling events. Our findings provide new insights into intestinal cell Ca²⁺ signaling mechanisms and establish C. elegans as a powerful model system for defining the gene networks and molecular mechanisms that underlie the generation and regulation of Ca²⁺ oscillations and intercellular Ca²⁺ waves in nonexcitable cells.

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