Scanning of the glucagon-like peptide-1 receptor localizes G protein-activating determinants primarily to the N terminus of the third intracellular loop
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It is well known that glucagon-like peptide-1 (7-36 amide) (tGLP-1) is a potent insulinotropic hormone with powerful antidiabetogenic effects. In the present study we sought to determine the precise regions of the intracellular domains of the tGLP-1 receptor that are required for its efficient coupling to adenylyl cyclase because cAMP is the primary candidate second messenger coupling tGLP-1 to insulin secretion. Recently, we identified an amino acid within the third intracellular loop, K334, that was required for efficient coupling of tGLP-1 receptor to adenylyl cyclase. A similar mutagenesis-based strategy was employed here to examine the first and second intracellular loops and to further define sequences in the third loop required for the efficient coupling of the receptor to its second messengers. Receptor mutants were expressed in COS-7 cells and examined for tGLP-1 binding and cAMP stimulation. Three alanine substitution mutations, V327A, 1328A, and V331A, resulted in significantly lower tGLP-1-stimulated cAMP production without reductions in receptor expression. Analysis of the first and second intracellular loops revealed only one mutation contained within the first loop, R176A, where a significant reduction in cAMP activation was observed with normal receptor expression. These studies suggest that specific determinants of coupling for tGLP-1 receptor are primarily localized to the predicted junction of the fifth transmembrane helix and the third intracellular loop. We predict that V327, 1328, and V331 form part of a hydrophobic face that directly contacts the G protein.
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In both group B and group C surreal-GPCRs, the third intracellular loop (ic3) and the C-terminal tail show high divergence, as is common for GPCRs in general.
“In both group B and group C surreal-GPCRs, the third intracellular loop (ic3) as well as the C-terminal tail show a high divergence, as common for GPCRs in general (Mathi et al., 1997).”
From Opsins and clusters of sensory G-protein-coupled receptors in the sea urchin genome (2006) · cites this paper as Mathi et al., 1997
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Disease-causing helix-8 mutations reprogram parathyroid hormone receptor-1 effector selectivity
Höppner, J., Stępniewski, T. M., Dean, T., Dieguez-Eceolaza, M., Tran, L. M.-L., Gellman, S. H., Cheloha, R. W., Inoue, A., Selent, J., Jüppner, H., et al. (2026) · Cell chemical biology · doi:10.1016/j.chembiol.2026.09.013
Signalling and Regulation of the Glucagon-like Peptide-1 receptor
Lu, J. N. (2014) · Figshare
- Authors
- Mathi, S. K., Chan, Y., Li, X., & Wheeler, M. B.
- Affiliations
- University of Toronto (CA)
- Corresponding author
- Wheeler, Michael B.
- ORCID
- Wheeler, Michael B.
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 1997-04-01
- Volume
- 11
- Issue
- 4
- Pages
- 424-432
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- OpenAlex
- W2043983076
- Cited by
- 71
- References
- 33
- Citations by year
- 2026: 1 · 2022: 2 · 2021: 1 · 2018: 1 · 2017: 1 · 2016: 5 · 2015: 4 · 2014: 5 · 2013: 6 · 2012: 3
- FWCI
- 0.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Diabetes Association
- University of Toronto
- Medical Research Council Canada
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- GLP-1 receptor, G protein coupling, third intracellular loop, cAMP signaling, adenylate cyclase, receptor mutagenesis, insulin secretion, G protein binding
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Cyclic AMP, Amino Acid Sequence, Animals, Binding Sites, Binding, Competitive, Cytoplasm, Models, Chemical, Molecular Sequence Data, Protein Conformation, Signal Transduction, Mutagenesis, Site-Directed, Protein Folding, Receptors, Glucagon, GTP-Binding Proteins, COS Cells
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