The concept of ‘kokumi’, which refers to an enhanced and more delicious flavor of food, has recently generated considerable interest in food science. However, kokumi has not been well studied in gustatory physiology, and the underlying neuroscientific mechanisms remain largely unexplored. Our previous research demonstrated that ornithine (L-ornithine), which is abundant in shijimi clams, enhanced taste preferences in mice. The present study aimed to build on these findings and investigate the mechanisms responsible for kokumi in rats. In two-bottle preference tests, the addition of ornithine, at a low concentration that did not increase the favorability of this substance alone, enhanced the animals’ preferences for umami, sweet, fatty, salty, and bitter solutions, with the intake of monosodium glutamate showing the most significant increase. Additionally, a mixture of umami and ornithine synergistically induced significant responses in the chorda tympani nerve, which transmits taste information to the brain from the anterior part of the tongue. The observed preference enhancement and increase in taste-nerve response were abolished by antagonists of the G-protein-coupled receptor family C group 6 subtype A (GPRC6A). Furthermore, immunohistochemical analysis indicated that GPRC6A was expressed in a subset of type II taste cells in rat fungiform papillae. These results provide new insights into flavor-enhancement mechanisms, confirming that ornithine is a kokumi substance and GPRC6A is a novel kokumi receptor.

Thermal nociception in Caenorhabditis elegans is regulated by the Ca²⁺/calmodulin-dependent protein kinase CMK-1, but its downstream effectors have remained unclear. Here, we combined in vitro kinase assays with mass-spectrometry-based phosphoproteomics to identify hundreds of CMK-1 substrates, including the calcineurin A subunit TAX-6, phosphorylated within its conserved regulatory domain. Genetic and pharmacological analyses reveal multiple antagonistic interactions between CMK-1 and calcineurin signaling in modulating both naive thermal responsiveness and adaptation to repeated noxious stimuli. Cell-specific manipulations indicate that CMK-1 acts in AFD and ASER thermo-sensory neurons, while TAX-6 functions in FLP thermo-sensory neurons and downstream interneurons. Since CMK-1 and TAX-6 act in distinct cell types, the phosphorylation observed in vitro might not directly underlie the behavioral phenotype. Instead, the opposing effects seem to arise from their distributed roles within the sensory circuit. Overall, our study provides (1) a resource of candidate CMK-1 targets for further dissecting CaM kinase signaling and (2) evidence of a previously unrecognized, circuit-level antagonism between CMK-1 and calcineurin pathways. These findings highlight a complex interplay of signaling modules that modulate thermal nociception and adaptation, offering new insights into potentially conserved mechanisms that shape nociceptive plasticity and pain (de)sensitization in more complex nervous systems.