A human glucagon-like peptide-1 receptor polymorphism results in reduced agonist responsiveness.
Glucagon-like peptide-1 (GLP-1) and its cognate receptor play an important physiological role in maintaining blood glucose homeostasis. A GLP-1 receptor (GLP-1R) polymorphism in which threonine 149 is substituted with a methionine residue has been recently identified in a patient with type 2 diabetes but was not found in non-diabetic control subjects. We have functionally assessed the recombinant GLP-1R variant after transient expression in COS-7 and HEK 293 cells. Compared to the wild type receptor, the variant GLP-1R showed (i) similar expression levels, (ii) 60-and 5-fold reduced binding affinities, respectively, for two GLP-1R full agonists, GLP-1 and exendin-4, and (iii) markedly decreased potencies of these peptides in triggering cAMP-mediated signaling (despite conserved efficacies). In contrast to full agonists, the efficacy of the primary GLP-1 metabolite/GLP-1R partial agonist, GLP-1 (9-36) amide, was essentially abolished by the T149M substitution. By hydropathy analysis, the polymorphism localizes to transmembrane domain 1, suggesting this receptor segment as a novel determinant of agonist affinity/efficacy. These findings reveal that naturally occurring sequence variability of the GLP-1R within the human population can result in substantial loss-of-function. A genetic link between the T149M variant and increased susceptibility to type 2 diabetes remains to be established.
Beinborn
Martin
M
Molecular Pharmacology Research Center, Molecular Cardiology Research Institute, Tufts-New England Medical Center, Mailbox 7703, 750 Washington Street, Boston, MA 02111, USA. MBeinborn@Tufts-NEMC.org
Worrall
Christine I
CI
McBride
Edward W
EW
Kopin
Alan S
AS
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000077270:Exenatide; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010455:Peptides / Q000737:chemistry; D011110:Polymorphism, Genetic; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D018027:Receptors, Glucagon / Q000819:agonists* / Q000235:genetics*; D011994:Recombinant Proteins / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D012984:Software; D014158:Transcription, Genetic; D014688:Venoms / Q000737:chemistry
D018076:DNA, Complementary; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D008024:Ligands; D010455:Peptides; D043562:Receptors, G-Protein-Coupled; D018027:Receptors, Glucagon; D011994:Recombinant Proteins; D014688:Venoms; D000077270:Exenatide; D000242:Cyclic AMP; D005947:Glucose