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

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

Posterior body wall muscle contraction (pBoc) in the nematode Caenorhabditis elegans occurs rhythmically every 45–50 s and mediates defecation. pBoc is controlled by inositol-1,4,5-trisphosphate (IP₃)–dependent Ca²⁺ oscillations in the intestine. The intestinal epithelium can be studied by patch clamp electrophysiology, Ca²⁺ imaging, genome-wide reverse genetic analysis, forward genetics, and molecular biology and thus provides a powerful model to develop an integrated systems level understanding of a nonexcitable cell oscillatory Ca²⁺ signaling pathway. Intestinal cells express an outwardly rectifying Ca²⁺ (ORCa) current with biophysical properties resembling those of TRPM channels. Two TRPM homologues, GON-2 and GTL-1, are expressed in the intestine. Using deletion and severe loss-of-function alleles of the gtl-1 and gon-2 genes, we demonstrate here that GON-2 and GTL-1 are both required for maintaining rhythmic pBoc and intestinal Ca²⁺ oscillations. Loss of GTL-l and GON-2 function inhibits I_ORCa 70% and 90%, respectively. I_ORCa is undetectable in gon-2;gtl-1 double mutant cells. These results demonstrate that (a) both gon-2 and gtl-1 are required for ORCa channel function, and (b) GON-2 and GTL-1 can function independently as ion channels, but that their functions in mediating I_ORCa are interdependent. I_ORCa, I_GON-2, and I_GTL-1 have nearly identical biophysical properties. Importantly, all three channels are at least 60-fold more permeable to Ca²⁺ than Na⁺. Epistasis analysis suggests that GON-2 and GTL-1 function in the IP₃ signaling pathway to regulate intestinal Ca²⁺ oscillations. We postulate that GON-2 and GTL-1 form heteromeric ORCa channels that mediate selective Ca²⁺ influx and function to regulate IP₃ receptor activity and possibly to refill ER Ca²⁺ stores.

Abbreviations used in this paper: CICR, Ca²⁺-induced Ca²⁺ release; CRAC, Ca²⁺ release–activated Ca²⁺; dsRNA, double-stranded RNA; IP₃, inositol-1,4,5-trisphosphate; ORCa, outwardly rectifying Ca²⁺; pBoc, posterior body wall muscle contraction; SERCA, sarco/endoplasmic reticulum Ca²⁺ ATPase; SOCC, store-operated Ca²⁺ channel.

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