Glucagon directly interacts with vagal afferent nodose ganglion neurons to induce Ca2+ signaling via glucagon receptors

•Glucagon ip injection induced ERK1/2 phosphorylation in nodose ganglion (NG).•Glucagon receptor mRNA is expressed in NG neurons.•Glucagon increases [Ca2+]i in NG neurons.•Glucagon-induced [Ca2+]i increase is suppressed by glucagon receptor antagonist.•Glucagon-responsive NG neurons also respond to insulin and cholecystokinin. Glucagon is released from the pancreatic islets postprandially and under hypoglycemic and cold conditions, and regulates glucose metabolism, feeding, energy expenditure and heat production, the functions partly controlled by the brain. Peripheral glucagon could signal to the brain via passing through the blood–brain barrier and/or acting on the vagal afferent. However, the latter remains to be determined. The present study aimed to clarify whether glucagon directly interacts with the nodose ganglion (NG) neurons of vagal afferent nerves in mice. In vivo study showed that intraperitoneal injection of glucagon induced phosphorylation of extracellular signal regulated kinase 1 and 2 (ERK1/2), cellular activation makers, in NG neurons. In fura-2 microfluorometric studies, glucagon increased cytosolic Ca2+ concentration ([Ca2+]i) in single NG neurons. The glucagon-induced [Ca2+]i increases were suppressed by a glucagon receptor antagonist, des-His1-[Glu9]-Glucagon (1–29) amide, and the glucagon receptor mRNA was expressed in NG neurons. The majority of glucagon-responsive NG neurons exhibited [Ca2+]i responses to insulin and cholecystokinin-8, the hormones that are secreted postprandially and implicated in satiety. These results demonstrate that glucagon, by interacting with the glucagon receptor, directly activates vagal afferent nerves, possibly being relayed to the signaling to the brain and formation of satiety.