GLP-1R (human, recombinant; aa 24-145) (Fc-tagged)

Glucagon-like peptide 1 receptor (GLP-1R) is a transmembrane G protein-coupled receptor (GPCR) and a member of the secretin family of receptors.¹ It is composed of extracellular and transmembrane domains responsible for ligand binding and an intracellular domain responsible for signaling.^1,2 It is primarily expressed in β-cells of the pancreas but also in adipocytes and pancreatic acinar cells, as well as the brain, kidney, stomach, and heart.³ When glucose levels are high, the incretin hormone GLP-1 binds to GLP-1R, which couples to Gα_s and induces signaling through the cAMP/PKA pathway to stimulate insulin biosynthesis, potentiate insulin secretion, reduce glucagon secretion, and slow gastrointestinal mobility to increase satiety.^1,3 GLP-1R can couple to either Gα_s, Gα_i/o, or Gα_q and recruit β-arrestin to varying degrees in response to different agonists, a phenomenon known as biased agonism, with lower β-arrestin recruitment following activation by agonists with improved antidiabetic effects. Loss-of-function mutations in GLP1R are associated with reduced insulin secretion, which can be rescued in vitro with certain GLP-1R agonists and positive allosteric modulators (PAMs).⁴ GLP1R variants that impair cell surface expression of GLP-1R are associated with impaired glucose control, as well as increased adiposity, body mass index, and glycated hemoglobin A1c (Hb1Ac). Cayman’s GLP-1R (human, recombinant; aa 24-145) (Fc-tagged) protein is a disulfide-linked homodimer. The reduced monomer, composed of GLP-1R (24-145) fused to human IgG1 Fc at its C-terminus, consists of 360 amino acids, has a calculated molecular weight of 41 kDa, and a predicted N-terminus of Arg24 after signal peptide cleavage. As a result of glycosylation, the monomer migrates at approximately 52.3 kDa by SDS-PAGE under reducing conditions.

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1. El Eid, L., Reynolds, C., Tomas, A., et al. Biased agonism and polymorphic variation at the GLP-1 receptor: Implications for the development of personalised therapeutics. Pharmacol. Res. 184, 106411 (2022).

2. Song, G., Yang, D., Wang, Y., et al. Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators. Nature 546(7657), 312-315 (2017).

3. Müller, T.D., Finan, B., Bloom, S.R., et al. Glucagon-like peptide 1 (GLP-1). Mol. Metab. 30, 72-130 (2019).

4. Gao, W., Liu, L., Huh, E., et al. Human GLP1R variants affecting GLP1R cell surface expression are associated with impaired glucose control and increased adiposity. Nat. Metab. 5(10), 1673-1684 (2023).