High protein diets are effective at promoting weight loss and stimulating the secretion of pancreatic hormones. Understanding the mechanisms underlying these effects may highlight new potential therapeutic targets. The calcium sensing receptor (CaSR) is stimulated by calcium and plays a critical role in calcium homeostasis. However, it is also found in many tissues unrelated to calcium regulation. CaSR activity can be modulated by aromatic amino acids, most potently by L-Phenylalanine, and CaSR has been suggested to act as a nutrient sensor mediating some of the physiological effects of protein intake. Previous work from our group found L-Phenylalanine drives anorectic gut hormone release and satiety, partly via the CaSR. Oral administration of L-Phenylalanine to mice also stimulates the secretion of the pancreatic hormones, insulin and glucagon. However, the mechanisms underlying these effects are unclear. The vagus nerve sends both afferent sensory and efferent motor signals between the brain and peripheral organs such as the gut and pancreas. Interestingly, vagal sensory afferents express the CaSR. Orally administered L-Phenylalanine stimulated c-Fos like immunoreactivity in the brainstem of mice and rats, the site of vagal innervation. Additionally, CaSR synthetic agonists modulate vagal activity in vitro. Using mice with a floxed CaSR gene and injecting cre expressing adeno-associated virus into the nodose ganglia, where the cell bodies of vagal afferents reside, we were able to selectively knockdown CaSR expression in the vagus nerve. This had no effect on L-Phenylalanines anorectic effects, but blunted L-Phenylalanines ability to stimulate glucagon secretion. This suggests that vagal CaSR may play an important role in mediating amino acid induced pancreatic hormone secretion. Further studies are required to determine the importance of vagal CaSR in the regulation of pancreatic hormone secretion, and whether this pathway is conserved in humans and can be exploited to develop novel anti-diabetic therapies.