Substance P plays an important role in cell adhesion molecule 1-mediated nerve–pancreatic islet α cell interaction

• Pancreatic islet α cells are activated by attached neurite stimulation.
• Cell adhesion molecule 1 promotes nerve–islet α cell interaction.
• Pancreatic islet α cells express neurokinin-1 receptors.
• Substance P is an important mediator in nerve–islet α cell interaction.

Autonomic neurons innervate pancreatic islets of Langerhans and maintain blood glucose homeostasis by regulating hormone levels. We previously showed that cell adhesion molecule 1 (CADM1) mediated the attachment and interaction between nerves and aggregated pancreatic islet α cells. In this study, we cocultured αTC6 cells, a murine α cell line, with mouse superior cervical ganglion (SCG) neurons. The oscillation of intracellular Ca2+ concentration ([Ca2+]i) was observed in 27% and 14% of αTC6 and CADM1-knockdown αTC6 cells (αTC6siRNA-CADM1 cells) in aggregates, respectively, within 1 min after specific SCG nerve stimulation with scorpion venom. In αTC6siRNA-CADM1 cells, the responding rate during 3 min after SCG nerve stimulation significantly increased compared with that within 1 min, whereas the increase in the responding rate was not significantly different in αTC6 cells. This indicated that the response of αTC6 cells according to nerve stimulation occurred more rapidly and effectively than that of αTC6siRNA-CADM1 cells, suggesting CADM1 involvement in promoting the interaction between nerves and α cells and among α cells. In addition, because we found that neurokinin (NK)-1 receptors, which are neuropeptide substance P receptors, were expressed to a similar extent by both cells, we investigated the effect of substance P on nerve–α cell interaction. Pretreatment with CP99,994 (0.1 μg/ml), an NK-1 receptor antagonist, reduced the responding rate of both cells, suggesting that substance P released from stimulated neurites was a mediator to activate αTC6 cells. In addition, α cells that were attached to neurites in a CADM1-mediated manner appeared to respond effectively to neurite activation via substance P/NK-1 receptors.