Signal bias at glucagon family receptors: rationale and downstream impacts

Abstract

AbbreviationscAMP Cyclic adenosine monophosphate DERET Diffusion-enhanced resonance energy transfer DPP-4 Dipeptidyl dipeptidase-4 GCG Glucagon GCGR Glucagon receptor GIP Glucose-dependent insulinotropic polypeptide GIPR Glucose-dependent insulinotropic polypeptide receptor GLP-1 Glucagon-like peptide-1 GLP-1R Glucagon-like peptide-1 receptor NEP24.11 Neutral endopeptidase T2D Type 2 diabetes TR-FRET Time-resolved Förster resonance energy transfer AbstractReceptors for the peptide hormones glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon (GCG) are important regulators of insulin secretion and energy metabolism. Here we sought to investigate how signal bias between cyclic AMP and βarrestin-2 recruitment can modulate the effects of prolonged agonist stimulation at each of these receptors. We generated analogues of GLP-1, GCG and GIP which in some cases showed selective reduction in β-arrestin-2 recruitment versus cAMP signalling compared to the parent peptide. Despite reduced acute signalling potency and/or efficacy, some biased GLP-1 and GIP analogues increased maximal sustained insulin secretion, although only at high agonist concentrations. Biased GCG analogues did not affect maximal insulin release from beta cells, or glucose output in hepatocytes.

Insights into agonist-elicited activation of the human glucose-dependent insulinotropic polypeptide receptor

“…Like all class B1 GPCRs, Gs-mediated production of cAMP is the most efficiently coupled second messenger pathway downstream of GIPR activation, critical to the physiological signaling of the receptor [9,40]. In the current study, this pathway is highly amplified providing robust responses even for mutants with low cell surface expression.…”

“…Four of the mutants Y145 1.47 A, P195 ECL1 A, T223 3.36 A and V227 3.40 A that had very low cell surface expression (Figure 2) did not display a robust response even at the highest concentration of 1 µM, while R190 2.67 A and R300 5. 40 A had low potency responses that could not be confidently fit to the model and were not quantified (Figure 7, Table 1, Table 2).…”

Variation in responses to incretin therapy: Modifiable and non-modifiable factors

“…This beneficial effect is evident in the G protein-biased agonist Exendin-phe1, derived from a single phenylalanine substitution at position 1 in Exenatide, which displays improved receptor recycling, reduced receptor desensitization, and sustained incretin-stimulated insulin secretion (Jones et al, 2018). Similar G protein-biased agonists have also been developed for the GIPR and the GCGR, but the full extent of their effects on beta cell function is still unknown (Jones et al, 2021).…”

“…Receptor trafficking involves the internalisation of the active receptor: Ligand complex towards endocytic compartments, followed by its deactivation/dephosphorylation and recycling back to the cell membrane, leading to its re-sensitisation, or trafficking to lysosomal organelles for its degradation and final signal termination (McGlone et al, 2021). Additional receptor destinations involve retrograde transport towards the Golgi apparatus (Bonifacino and Rojas, 2006) or receptor incorporation into exosomes intended to be secreted, potentially playing a role in inter-cellular communication (Isola and Chen, 2016).…”

Partial agonism improves the anti-hyperglycaemic efficacy of an oxyntomodulin-derived GLP-1R/GCGR co-agonist

“…two of the most proximal interactors recruited to the activated receptor, as well as their corresponding signalling intermediates. Both GLP-1R and GCGR are primarily coupled to cAMP generation through Gα s activation, with recruitment of β arrestins being associated with receptor desensitisation, endocytosis and diminished long term functional responses [16,17]. Whilst the therapeutic benefits of biased GLP-1R agonism have been demonstrated in preclinical studies on a number of occasions [18][19][20][21], the application of this principle to GLP-1R/GCGR co-agonism is less explored.…”