Evolutionary conservation and adaptability of cholecystokinin neuropeptide signaling in the sea cucumber Apostichopus japonicus

Food ingestion is fundamental for animal survival and growth, with the cessation of feeding upon nutrient fulfillment being tightly regulated by a variety of satiety factors. Notably, sulfakinin/cholecystokinin (SK/CCK)-type neuropeptide signaling has been identified as an inhibitory regulator of food intake across the animal kingdom. However, its regulatory mechanism in feeding in deuterostome invertebrates remains unclear. Here, we characterized SK/CCK-type signaling in a deuterostome invertebrate, the sea cucumber Apostichopus japonicus (phylum Echinodermata). A single SK/CCK-type precursor in A. japonicus generates two mature peptides (AjSK/CCK1, AjSK/CCK2) that activate a shared receptor (AjSK/CCKR), triggering Ca 2+ mobilization via the Gαq-dependent pathway and extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation. Both peptides induce dose-dependent contraction of longitudinal muscles, while AjSK/CCK2 additionally elicits sustained contraction of the posterior intestine, an effect absent in other gut regions. Long-term injection of both peptides reduces food intake and significantly downregulates orexin-type neuropeptide genes ( AjOrexin1P , AjOrexin2P ) in the circumoral nerve ring (CNR) and intestine. Unlike mammals, where CCK inhibits feeding by contracting the pyloric sphincter to delay gastric emptying, SK/CCK-type peptides in sea cucumbers exert their anorexic effect in part by selectively contracting the posterior intestine, thereby inhibiting intestinal emptying. This divergence in action sites highlights the evolutionary adaptability of SK/CCK-type signaling as a conserved inhibitory regulator of feeding across bilaterian animals. Elucidating these mechanisms in the economically important A. japonicus may inform development of appetite-promoting agents for sustainable aquaculture. The feeding inhibition mechanism of SK/CCK-type neuropeptides: mammals vs sea cucumbers. In mammals (left) and sea cucumbers (right), SK/CCK-type neuropeptides inhibit feeding via a dual-pathway mechanism: 1) Neural regulation: downregulating expression of the orexigenic factor orexin in the central nervous system to reduce appetite, and the conserved interaction between SK/CCK and orexin in feeding regulation, from deuterostome invertebrates to mammals, highlights the evolutionary conservation of neuropeptide function; 2) Mechanical regulation: contracting the pyloric sphincter (mammals) or posterior intestine (sea cucumbers) to inhibit gastric or intestinal emptying, and this divergence in action sites reflects the evolutionary adaptability of neuropeptide function.