Invertebrate Bile Acid‐Sensitive Ion Channels and Their Emergence in Bilateria

The broad Degenerin/epithelial sodium channel (DEG/ENaC) family includes a subfamily of bile acid-sensing ion channels (BASICs). While their biophysical properties are extensively studied in mammals, the presence and function of BASICs in invertebrates remain largely unexplored. Here, we present the first functional evidence of invertebrate BASICs, revealing conserved features and evolutionary adaptations across bilaterian species. Using electrophysiological and pharmacological approaches, we show that invertebrate BASICs exhibit species-specific bile acid sensitivity profiles and differing responses to channel blockers, amiloride, and diminazene, while retaining shared properties like inhibition by calcium ions and selective permeability of sodium ions. For example, the acorn worm Schizocardium californicum BASIC displays broad bile acid sensitivity similar to mammals, while the brachiopod Novocrania anomala BASIC is activated solely by ursodeoxycholic acid (UDCA) in our experiments. Mutagenesis of the conserved D444 residue in the pore-lining region confirms its critical role in gating. Combined functional and phylogenetic analysis suggests BASICs emerged early in bilaterian evolution, evolving from channels that were merely modulated by bile acids, like their acid-sensing ion channel cousins, into channels that are activated by bile acids. Tissue-specific expression patterns imply roles in bile acid-dependent sodium absorption or environmental sensing of bile acid-like compounds. Given the absence of endogenous bile acids in invertebrates, we propose that invertebrate BASICs may detect environmental compounds, contributing to ecological interactions. This study enhances our understanding of the evolutionary, functional, and ecological roles of BASICs, with implications for future research into their native ligands.