title: Regulation of glucagon-like peptide-1 receptor and calcium-sensing receptor signaling by L-histidine.
abstract: 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 rat insulinoma (INS-1) cells and find that the predicted amino acid sequence of the receptor is identical with 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 nonspecific 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. Coexpression 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 reporter activity in INS-1 cells and in human embryonic kidney-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.
authors.affiliation: Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Howard Hughes Medical Institute, Harvard Medical School, 50 Blossom Street, Boston, Massachusetts 02114, USA. leech@helix.mgh.harvard.edu
authors.forename: Colin A
authors.initials: CA
authors.lastname: Leech
authors.forename: Joel F
authors.initials: JF
authors.lastname: Habener
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D045604:Extracellular Fluid / Q000378:metabolism; D017930:Genes, Reporter / Q000187:drug effects; D005934:Glucagon / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D006639:Histidine / Q000494:pharmacology*; D006801:Humans; D009994:Osmolar Concentration; D010446:Peptide Fragments / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D011498:Protein Precursors / Q000494:pharmacology; D012313:RNA / Q000378:metabolism; D051381:Rats; D044169:Receptors, Calcium-Sensing / Q000235:genetics / Q000378:metabolism*; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C000593833:GLP1R protein, human; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D010446:Peptide Fragments; D011498:Protein Precursors; D044169:Receptors, Calcium-Sensing; D018027:Receptors, Glucagon; D006639:Histidine; D012313:RNA; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000242:Cyclic AMP; D037342:Pertussis Toxin; D002118:Calcium