Keywords: GLP-1R, Class B GPCR, cAMP signaling, biased agonism, incretin, metabolic diseases

The glucagon-like peptide-1 receptor (GLP-1R) is a key member of the Class B1 G protein-coupled receptor (GPCR) family and plays a critical role in glucose homeostasis regulation. Since the approval of the first GLP-1 receptor agonist (GLP-1RA), exenatide, for type 2 diabetes treatment in 2005, this target has become one of the most successful in metabolic disease drug development. The emergence of next-generation drugs like semaglutide and tirzepatide has further expanded the therapeutic applications of GLP-1R from glycemic control to obesity management, cardiovascular protection, and even neurodegenerative diseases. Understanding the molecular structure, signal transduction mechanisms, and tissue distribution of GLP-1R is fundamental to deciphering the action principles of existing drugs and designing next-generation molecules.

GLP-1R belongs to the Class B1 secretin/glucagon subfamily of GPCRs. Like typical GPCRs, its structure consists of seven transmembrane helices (TM1-TM7) and includes a large extracellular domain (ECD). The ECD plays a critical role in ligand recognition—the C-terminus of endogenous GLP-1 first binds to the receptor's ECD, after which its N-terminus inserts into the core of the transmembrane domain, inducing conformational rearrangement of the receptor.

Recent structural pharmacology studies, using techniques such as cryo-electron microscopy, X-ray crystallography, and mass spectrometry, have systematically mapped the conformational changes of GLP-1R from its inactive to active state. Activation of GLP-1R involves significant conformational changes in both the extracellular and transmembrane domains, which drive downstream signal transduction. Specifically, ligand binding triggers rearrangement of the transmembrane helices and opening of the intracellular loops, creating space for G protein binding.

Different ligand binding modes can lead to distinct receptor conformational states. Research shows that agonists with varying functions (e.g., the small-molecule biased agonist CHU-128, the small-molecule balanced agonist danuglipron, and the peptide-based balanced agonist Peptide 19) exhibit unique binding patterns and induce distinct helical packing arrangements. These differences have been revealed at the atomic level through full-atom molecular dynamics simulations.

GLP-1R primarily couples with Gαs protein, and upon activation, it promotes the production of the second messenger cAMP by adenylate cyclase (AC). cAMP subsequently activates protein kinase A (PKA) and exchange protein directly activated by cAMP (EPAC), regulating a series of biological effects such as insulin secretion, gene transcription, and cellular metabolism. This is the main signaling pathway of GLP-1R and the core molecular basis of its glycemic and weight-loss effects.

However, GLP-1R's signal output is not limited to a single mode. Similar to other members of the Class B1 family, GLP-1R exhibits signal pleiotropy—it can couple not only with Gαs but also with other Gα family members and recruit β-arrestins. Specifically, GLP-1R can couple with secondary G proteins such as Gαq and Gαi. Additionally, phosphorylation is a key determinant in the formation of GPCR-βarr complexes between GLP-1R and GIPR.

GLP-1R also has a unique property in signal regulation: substantial experimental evidence indicates that GLP-1R does not undergo desensitization in physiologically relevant tissues but instead produces potent and sustained cAMP signaling. This characteristic may stem from the continuous cycling of GLP-1R between the cell membrane and caveolae/lipid rafts. In contrast, GIPR signaling is broadly mediated by β-arrestins and undergoes significant desensitization, internalization, and downregulation. Furthermore, post-endocytic sorting also affects GLP-1R signaling: GASP-1-mediated GLP-1R trafficking may contribute to the tolerance mechanisms observed with long-term use of incretin-based drugs.

Receptor activity-modifying proteins (RAMPs) are a class of auxiliary proteins that can modulate the pharmacological properties of GPCRs. Research has found that GLP-1R interacts with RAMP3, forming a heterodimer capable of binding agonists at the cell surface. The expression of RAMP3 shifts the receptor's signaling preference from the classical cAMP-driven pathway to Ca²⁺ mobilization.

At the G protein coupling level, RAMP3 interaction reduces GLP-1R's activation of Gαs but enhances its secondary coupling with Gαq and Gαi. This shift in signaling preference has functional consequences: when RAMP3-overexpressing cells are stimulated with GLP-1, glucose-stimulated insulin secretion is significantly enhanced. Conversely, in Ramp3 knockout mice, reduced endogenous RAMP3 expression leads to decreased sensitivity to GLP-1. This discovery provides a new regulatory dimension for developing next-generation GLP-1R agonists with tissue selectivity or distinct signaling profiles.

The expression distribution of GLP-1R determines the broad biological effects of its agonists.

Pancreas: GLP-1R promotes glucose-dependent insulin secretion in pancreatic β-cells—the primary mechanism of its glucose-lowering effect; it inhibits glucagon secretion in α-cells and regulates somatostatin secretion in δ-cells.

Central Nervous System: Activation of central GLP-1R can suppress neuroinflammation, reduce β-amyloid (Aβ) deposition, promote neurogenesis, and decrease α-synuclein aggregation. GLP-1R activation also mitigates neuroinflammation, inhibits oxidative stress, reduces apoptosis, and maintains neuronal function.

Gastrointestinal Tract: GLP-1R activation delays gastric emptying, aiding in postprandial glucose control and enhancing satiety.

Cardiovascular System and Kidneys: These also express GLP-1R. GLP-1RAs have demonstrated cardiovascular protective effects in clinical settings.

"Biased agonism" is one of the most cutting-edge concepts in GLP-1R drug development. Its core idea is that different ligands binding to the same receptor can induce distinct receptor conformations, preferentially activating one signaling pathway (e.g., G protein pathway) over another (e.g., β-arrestin pathway).

A 2025 study published in Nature Communications provided key evidence: in mouse models, signaling bias was significantly correlated with GLP-1R agonist-mediated weight loss. The study further demonstrated that biased agonism is a strong predictor of in vivo efficacy for GLP-1R agonists—independent of intrinsic cAMP potency or pharmacokinetic factors.

Based on this principle, next-generation cAMP-biased GLP-1R agonists have entered clinical development. Pfizer's enoglutide is the first cAMP-biased GLP-1R agonist approved globally, showing a 35% greater weight reduction and 20% greater waist circumference reduction compared to semaglutide in head-to-head studies.

Notably, not all GLP-1R agonists aim for strong cAMP bias. Some researchers propose that GLP-1R can be phenotypically regarded as a functionally Gs-selective receptor, a feature with important implications for designing multi-target ligands.

The clinical development of GLP-1R agonists has evolved from injectable peptides to oral small molecules.

Peptide-based agonists dominate the current market. Semaglutide achieves long-acting effects through fatty acid modification, enabling once-weekly dosing; tirzepatide, as a dual GLP-1R/GIPR agonist, further expands the therapeutic boundaries.

Oral small-molecule agonists are a hot research direction. At the 2026 ADA Annual Meeting, multiple clinical datasets for oral small-molecule GLP-1RAs were presented: AstraZeneca's elecoglipron achieved 10.5% weight loss at 26 weeks and 11.8% at 36 weeks in a Phase IIb study; Ascletis' ASC30 showed 7.7% placebo-adjusted weight loss at 13 weeks with a 60 mg maintenance dose and only 50% of the vomiting incidence seen with comparable products; Hengrui's HRS-7535 has completed Phase II trials in China's obese population. Eli Lilly's orforglipron has submitted for approval in China.

Ultra-long-acting formulations are also advancing rapidly. Berobenatide achieved a "once-monthly" dosing frequency in Phase IIb trials, with initial weight loss data reaching 12.3%.

As a clinically validated metabolic target, GLP-1R's molecular structure and signaling mechanisms have been thoroughly elucidated. From the conformational activation of Class B GPCRs, the balance between G protein coupling and β-arrestin recruitment, the regulatory role of RAMPs, to the systemic biological effects determined by tissue distribution, GLP-1R research serves as a paradigm for understanding GPCR signal regulation. The clinical translation of biased agonism is driving the development of next-generation molecules, while innovations in formulations—from oral small molecules to ultra-long-acting agents—continue to expand the therapeutic boundaries of this target. With further integration of multidisciplinary approaches such as structural biology, computational chemistry, and clinical pharmacology, GLP-1R-targeting drugs hold promise for unlocking their therapeutic potential in a broader range of diseases.