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Acid cam qt3/6/2023 ![]() This triggers the posterior body wall muscles to contract (pBoc), via activation of a proton-gated cation channel PBO-5/PBO-6 ( 22, 23). Increased cytosolic Ca 2+ results in the rhythmic release of protons from the basolateral membrane, into the pseudocoelom. IP 3 signaling loss-of-function mutations cause dramatic increases in both period length and variability, whereas overexpression of the IP 3 receptor, ITR-1, reduces period length ( 19– 21). The DMP depends on inositol 1,4,5-trisphosphate (IP 3)-dependent Ca 2+ oscillations in the intestinal epithelial cells. ![]() ![]() Acidification of the intestinal tract is also a hallmark of conditions such as irritable bowel syndrome and cystic fibrosis, so understanding the role of acid sensors, of which the ASICs are prime candidates, is of wide-ranging therapeutic importance ( 18). The extreme acidity of the stomach requires an elaborate system of mucosal protective mechanisms, failure of which results in conditions such as gastritis, ulceration and dyspepsia. However, less is known about their physiological role in non-neuronal tissue such as the intestinal epithelium, despite cross-phyla evidence for gastrointestinal expression and the role of acidity therein ( 14– 17). ASICs are widely expressed in the central and peripheral nervous system, where their roles in inflammation, ischemia, pain perception, and learning are extensively studied ( 8– 13). They are an important drug target, because acidosis is a feature of painful inflammatory and ischemic conditions. We take advantage of this short-period cellular oscillator to relate ion channel physiology in vivo to organismal metabolism and behavior.ĪSICs, the acid-sensing members of the Degenerin/Epithelial Sodium Channel (DEG/ENaC) superfamily of cation channels are thought to be the main proton receptors in vertebrates ( 6, 7). Here we examine the physiological role of acid-sensing ion channels (ASICs) in the defecation motor program (DMP) of the nematode Caenorhabditis elegans, an ultradian rhythm that occurs about every 50 seconds ( 3, 4). Disruption of biological clocks can have devastating consequences on homeostasis or behavior ( 5). The maintenance of such rhythms can rely on fluctuating gene expression, hormone concentrations, or homeostatic oscillations in signaling molecules within cellular compartments, depending on the timescale of the clock ( 1– 4). Many physiological processes occur with a predictable periodicity. We thus directly link the proton-sensing properties of these channels to their physiological roles in pH regulation and Ca 2+ signaling, the generation of an ultradian oscillator, and its metabolic consequences. flr-1 and acd-3/del-5 mutants show severe developmental and metabolic defects. ![]() ![]() In contrast, the second channel, composed of FLR-1, ACD-3 and/or DEL-5, located on the basolateral membrane, controls the intracellular Ca 2+ wave and forms a core component of the master oscillator that controls timing and rhythmicity of the DMP. An ACD-5-containing channel, on the apical membrane of the intestinal epithelium, is essential for maintenance of luminal acidity, and thus the rhythmic oscillations in lumen pH. Here, we identify two acid-sensing ion channels, with very different proton sensing properties, and describe their role in an ultradian clock, the defecation motor program (DMP) of the nematode Caenorhabditis elegans. Biological clocks are fundamental to an organism’s health, controlling periodicity of behavior and metabolism. ![]()
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