The odorant (R)-(-)-carvone promotes glucose-stimulated insulin secretion via the olfactory receptor Olfr1259 in pancreatic β-TC6 cells

Olfactory receptors (ORs) make up the largest subfamily of G protein-coupled receptors that are expressed in olfactory sensory neurons in the nasal cavity and recognize an enormous number of odorants from the external environment. These receptors, however, have also been found in many other tissues including pancreas, liver, and adipose tissue, in which they seem to play important but different roles. Yet, the exact functions of ORs in these extra-nasal tissues are not well understood. Here, we report that (R)-(-)-carvone and a few other odorants were able to evoke calcium responses in mouse pancreatic β-TC6 cells. Furthermore, (R)-(-)-carvone potentiated cytoplasmic cAMP accumulation and glucose-stimulated insulin secretion (GSIS). More importantly, GPCR signaling pathway components adenylyl cyclase, phospholipase C, and inositol triphosphate receptor were involved in (R)-(-)-carvone-induced signal transduction. By reanalyzing the available β-TC6 cells' RNAseq dataset, we identified several candidate ORs for (R)-(-)-carvone. Further analyses with molecular docking and molecular dynamics simulations indicated that (R)-(-)-carvone bound to the odorant-binding pocket of the olfactory receptor Olfr1259 while knockdown of Olfr1259 expression in β-TC6 cells with siRNA significantly reduced the stimulatory effects of (R)-(-)-carvone on cytoplasmic Ca²⁺ and cAMP levels, and insulin secretion. Together, these results indicated that Olfr1259 is the receptor for (R)-(-)-carvone in β-TC6 cells. Therefore, our study highlighted the important roles of (R)-(-)-carvone and its receptor Olfr1259 in initiating calcium signaling, inducing intracellular cAMP accumulation, and enhancing GSIS in pancreatic β cells, demonstrating that Olfr1259 may be a new therapeutic target for regulating glucose metabolism and for treating diabetes.