Calcium-Sensing Receptor Regulation of Gastrointestinal Hormone Secretion

The interaction of dietary nutrients with chemoreceptors in the gastrointestinal tract after a meal stimulates the secretion of gut hormones, which trigger the key processes of digestion and absorption, and also regulate energy intake and postprandial glycemia. One of these receptors, first recognized for its capacity to gauge extracellular calcium (Ca2+), is the calcium-sensing receptor (CaSR). Subsequent to its cloning, the CaSR was found to sense not only Ca2+, but also L-amino acids (AAs) and, based on solved protein structures, distinct binding sites have been reported for Ca2+ ions and the aromatic AA, L-tryptophan (L-Trp). In the stomach and small intestine, the CaSR is expressed in enteroendocrine cells, and a substantial body of preclinical work has demonstrated that it mediates gut hormone secretion in response to L-Trp and another aromatic AA, L-phenylalanine (L-Phe), and that extracellular Ca2+ promotes these effects. In humans, intraluminal administration of L-Trp or L-Phe increases plasma levels of gut hormones, associated with reductions in both energy intake and the plasma glucose response to a subsequent meal. In addition, co-administration of Ca2+ enhances the effect of L-Trp to increase plasma levels of gut hormones (including cholecystokinin, glucagon-like peptide-1 and peptide YY) and reduce energy intake. These observations have implications for the development of novel nutrient-based management strategies for obesity and type 2 diabetes. This review considers preclinical and clinical evidence that CaSR activators, including extracellular Ca2+ as well as the aromatic AAs, L-Trp and L-Phe, stimulate gut hormones and lower both energy intake and postprandial glycemia.