Selected tetrapeptides lead to a GLP-1 release from the human enteroendocrine cell line NCI-H716

Enteroendocrine cells in the intestine sense the luminal contents and have been shown to respond to not only fatty acids, proteins, and monosaccharides but also artificial sweeteners and bitter compounds. Secretion of hormones such as CCK and GLP-1 from these cells is often associated with a rise in intracellular calcium concentration [Ca²+](i). The human NCI-H716 enteroendocrine cell line has been described as a proper model to study GLP-1 secretion in response to amino acids and protein hydrolysates. Here, we describe that NCI-H716 cells specifically respond to selective tetrapeptides such as tetra-glycine, tetra-alanine and Gly-Trp-Gly-Gly with a dose-dependent [Ca²+](i) response and a GLP-1 secretion, whereas selected free amino acids, dipeptides, tripeptides and pentapeptides failed to elicit such a response. Hormone secretion was not associated with changes in cAMP levels in the cells. The calcium-dependence of hormone secretion appears to involve store-operated calcium channels (SOCCs), since the SOCC blocker 2-APB abolished both the [Ca²+](i) response and GLP-1 release upon tetra-glycine stimulation. The nature of the sensor currently remains elusive, and no obvious common structural pattern in tetrapeptides eliciting GLP-1 secretion was identified. This tetrapeptide sensing in NCI-H716 cells may be underlying the effective stimulation of hormone secretion shown for various protein hydrolysates, and could involve a novel G-protein-coupled receptor (GPCR).