Sustained wash-resistant receptor activation responses of GPR119 agonists

Eur J Pharmacol. 2015 Sep 5:762:430-42. doi: 10.1016/j.ejphar.2015.06.031. Epub 2015 Jun 20.


G protein-coupled receptor 119 (GPR119) is involved in regulating metabolic homoeostasis, with GPR119 agonists targeted for the treatment of type-2 diabetes and obesity. Using the endogenous agonist oleoylethanolamide and a number of small molecule synthetic agonists we have investigated the temporal dynamics of receptor signalling. Using both a dynamic luminescence biosensor-based assay and an endpoint cAMP accumulation assay we show that agonist-driven desensitization is not a major regulatory mechanism for GPR119 despite robust activation responses, regardless of the agonist used. Temporal analysis of the cAMP responses demonstrated sustained signalling resistant to washout for some, but not all of the agonists tested. Further analysis indicated that the sustained effects of one synthetic agonist AR-231,453 were consistent with a role for slow dissociation kinetics. In contrast, the sustained responses to MBX-2982 and AZ1 appeared to involve membrane deposition. We also detect wash-resistant responses to AR-231,453 at the level of physiologically relevant responses in an endogenous expression system (GLP-1 secretion in GLUTag cells). In conclusion, our findings indicate that in a recombinant expression system GPR119 activation is sustained, with little evidence of pronounced receptor desensitization, and for some ligands persistent agonist responses continue despite removal of excess agonist. This provides novel understanding of the temporal responses profiles of potential drug candidates targetting GPR119, and highlights the importance of carefully examining the the mechanisms through which GPCRs generate sustained responses.

Keywords: AR-231,453 (PubChem CID: 47069); ARN-II (PubChem CID: 16036825); AZ1 (PubChem CID: 51030901); AZ2 (PubChem CID: 51029876); AZ3 (PubChem CID: 56643412); Agonist; Binding kinetics; Desensitization; GPR119; GSK-1292263 (PubChem CID: 24996872); MBX-2982 (PubChem CID: 25025505); Membrane deposition; Sustained signalling; oleoylethanolamine (PubChem CID: 2583454).

MeSH terms

  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cyclic AMP / metabolism
  • HEK293 Cells
  • Humans
  • Kinetics
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism*


  • GPR119 protein, human
  • Receptors, G-Protein-Coupled
  • Cyclic AMP