Highly Ca(2+)-selective TRPM Channels Regulate IP(3)-dependent Oscillatory Ca(2+) Signaling in the C. elegans Intestine

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 (IP(3))–dependent Ca(2+) oscillations in the intestine. The intestinal epithelium can be studied by patch clamp electrophysiology, Ca(2+) 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 Ca(2+) signaling pathway. Intestinal cells express an outwardly rectifying Ca(2+) (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 Ca(2+) 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 Ca(2+) than Na(+). Epistasis analysis suggests that GON-2 and GTL-1 function in the IP(3) signaling pathway to regulate intestinal Ca(2+) oscillations. We postulate that GON-2 and GTL-1 form heteromeric ORCa channels that mediate selective Ca(2+) influx and function to regulate IP(3) receptor activity and possibly to refill ER Ca(2+) stores.