Receptor-specific agonists of the extracellular calcium-sensing receptor (CaSR) potentiate glucose-induced insulin secretion, an effect similar to that of glucagon-like peptide-1 (GLP-1). We have sequenced the full open reading frame of the CaSR from INS-1 cells and find that the predicted amino acid sequence of the receptor is identical to that of the receptor from the parathyroid gland. This receptor couples to both Gq/11 and Gi/o and this dual coupling may partly explain the varying effects of non-specific agonists on secretion reported previously. L-histidine (L-His) increases the sensitivity of the CaSR to extracellular Ca²⁺ and potentiates glucose-dependent insulin secretion from INS-1 cells. This potentiation is partially inhibited at low extracellular [Ca²⁺] where the CaSR is ineffective. Co-expression of the CaSR and GLP-1 receptor (GLP-1R) produces a pertussis toxin-sensitive inhibition of GLP-1-induced cAMP production in response to elevated extracellular [Ca²⁺]. However, L-His potentiates cAMP-response element (CRE) reporter activity in INS-1 cells and in HEK-293 cells expressing either the GLP-1R alone or the CaSR and GLP-1R. INS-1 cells express the RNA for the CaSR at a lower level than that for the GLP-1R. This difference in expression level of the receptors may explain the potentiation of insulin secretion by L-His despite coupling of the CaSR to Gi/o. In conclusion, L-His can potentiate both GLP-1R- and CaSR-activated signaling pathways and these effects may play a role in the potentiation of glucose-induced insulin secretion in response to meals containing protein in addition to carbohydrates and fat.