Results for “GCGR” | PubMed Health

PubMed2026

Structural basis for small-molecule agonism at GCGR and GIPR via a conserved intracellular allosteric site.

The glucagon receptor (GCGR) and gastric inhibitory polypeptide receptor (GIPR) are class B GPCRs that regulate glucose homeostasis and energy balance, making them key targets for type 2 diabetes and obesity. Achieving preferential Gs signaling at these receptors with small molecules remains an unmet challenge. Here, we report SIM1, developed through optimization of the PCO371 scaffold, which exhibits preferential Gs signaling at GCGR and GIPR with minimal detectable β-arrestin recruitment and substantially improved efficacy at GIPR. Cryo-EM structures of SIM1-GCGR-Gs (2.53 Å) and SIM1-GIPR-Gs (2.74 Å) reveal a shared intracellular allosteric interface at the receptor-G protein coupling region, distinct from extracellular peptide recognition. Structural comparison with GLP1R suggests that intracellular conformational constraints contribute to differential SIM1 responsiveness, which is restored by targeted mutations. Guided by these insights, analogs SIM2 and SIM3 exhibited up to 20-fold enhanced potency while maintaining an apparent preferential Gs signaling profile. These findings reveal a conserved intracellular allosteric activation mechanism across multiple class B GPCRs and identify SIM1 and its analogs as valuable chemical tools for investigating receptor-specific intracellular allosteric regulation and G protein-preferential signaling.

GCGR↗

PubMed2026

The effect of sex and endurance exercise training on the incretin signaling pathway in 17 rat tissues.

Incretin-based pharmacotherapies, particularly glucagon-like peptide-1 (GLP-1) receptor agonists, have transformed the treatment of type 2 diabetes, with demonstrated benefits across multiple organ systems. Their success has driven the investigation of related gut-derived hormones, most prominently dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists, but extend to other targets with similar metabolic functions. For this class of drugs, the extent to which organ health improvements are secondary to improved systemic glycemic control versus direct tissue signaling remains unclear, partly because receptor availability across tissues is poorly annotated. We leveraged data from the Molecular Transducers of Physical Activity Consortium to annotate incretin receptor expression across 17 tissues in Fischer 344 rats and the Genotype-Tissue Expression Portal for human-level receptor expression. Furthermore, given the role of exercise in the preservation of muscle mass during weight loss, we analyzed the effects of 1, 2, 4, or 8 wk of treadmill exercise training on incretin-related signaling at the epigenetic, transcript, and protein levels. Endurance training elicited sex- and tissue-specific changes in incretin receptor expression, including downregulation of Gcgr across brown adipose, adrenal glands, and white adipose tissue (WAT). Training-induced Gipr regulation occurred in the adrenal glands, brain cortex, and hippocampus. Collectively, these findings contribute to the map of incretin receptor biology and identify exercise-responsive regulatory axes that may underlie synergistic effects of exercise and incretin-based therapies on weight management and metabolic health.NEW & NOTEWORTHY This study provides the first multiomic, multitissue description of incretin signaling receptor expression and regulation in response to endurance exercise training. We identify time point and sex-specific changes in incretin signaling across tissues, highlighting training effects on Gcgr, Gipr, and Sctr regulation in the adrenals, WAT, and brain. These findings help establish an exercise-responsive incretin signaling axis that may identify interactions from incretin-based therapies and exercise-based lifestyle interventions.

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