Molecular mechanisms underlying physiological and receptor pleiotropic effects mediated by GLP‐1R activation

Abstract

The incidence of type 2 diabetes in developed countries is increasing yearly with a significant negative impact on patient quality of life and an enormous burden on the healthcare system. Current biguanide and thiazolidinedione treatments for type 2 diabetes have a number of clinical limitations, the most serious long-term limitation being the eventual need for insulin replacement therapy (Table 1). Since 2007, drugs targeting the glucagon-like peptide-1 (GLP-1) receptor have been marketed for the treatment of type 2 diabetes. These drugs have enjoyed a great deal of success even though our underlying understanding of the mechanisms for their pleiotropic effects remain poorly characterized even while major pharmaceutical companies actively pursue small molecule alternatives. Coupling of the GLP-1 receptor to more than one signalling pathway (pleiotropic signalling) can result in ligand-dependent signalling bias and for a peptide receptor such as the GLP-1 receptor this can be exaggerated with the use of small molecule agonists. Better consideration of receptor signalling pleiotropy will be necessary for future drug development. This is particularly important given the recent failure of taspoglutide, the report of increased risk of pancreatitis associated with GLP-1 mimetics and the observed clinical differences between liraglutide, exenatide and the newly developed long-acting exenatide long acting release, albiglutide and dulaglutide. LINKED ARTICLESThis article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://dx.doi. org/10.1111/bph.2014.171.issue-5 Abbreviations ADP, adenosine diphosphate; ANS, autonomic nervous system; ATP, adenosine triphosphate; Bad, Bcl-2-associated death promoter; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element binding protein; DPPIV, dipeptidyl peptidase IV; EGF-R1, epidermal growth factor receptor; Epac2, exchange protein directly activated by cAMP 2; GCGR, glucagon receptor; GIP, gastric inhibitory polypeptide; GLP-1, glucagon-like peptide-1; GLP-1R, glucagon-like peptide-1 receptor; GLP-2, glucagon-like peptide-2; GPCR, G protein-coupled receptor; GRK, G protein-coupled receptor kinase; GSIS, glucose stimulated insulin secretion; ICV, introcerebroventricular; KATP, ATP sensitive potassium channel (potassium inwardly-rectifying channel, subfamily J); MAPK, mitogen activated protein kinase; NFAT, nuclear factor of activated T-cells; PACAP, pituitary adenylate cyclase activating polypeptide; PDX-1, pancreatic-duodenum homeobox-1; PI3K, phosphoinositide 3-kinase; PKA, protein kinase A; Rab3A, Ras-associated protein 3A; Rap1, Ras-proximate-1; Rim2, regulating synaptic membrane exocytosis 2; SNAP25, synaptosomal-associated protein 25; T2DM, type 2 diabetes mellitus; VDCC, voltage-dependant calcium channel; VIP, vasoactive intestinal peptide The incretin effectThe observation that oral glucose administration results in significantly higher pancreatic insulin secretion compared with intravenous dosing...

Rearrangement of a polar core provides a conserved mechanism for constitutive activation of class B G protein-coupled receptors

“…Next we sought to evaluate whether the mutations in Met-338 or Phe-345 that cause constitutive G protein signaling could also result in ␤-arrestin1 recruitment to GCGR (27). To quantify interaction between GCGR and ␤-arrestin1, we adopted a previously developed Tango assay (18) in which the C-terminal tail of GCGR is fused with a tobacco etch virus (TEV) protease cleavage site and the transcriptional activator Relative basal activity (RBA), -fold increase in basal activity of the mutated receptors relative to the WT receptor.…”

A Hydrogen-Bonded Polar Network in the Core of the Glucagon-Like Peptide-1 Receptor Is a Fulcrum for Biased Agonism: Lessons from Class B Crystal Structures

“…These include promotion of insulin synthesis and release, decreased glucagon production, preservation of pancreatic b-cell mass, decreased appetite and gastric empyting, and preservation and promotion of cardiac function [reviewed in Baggio and Drucker (2007); Koole et al (2013); Pabreja et al (2014)]. GLP-1 acts via the GLP-1 receptor, a class B peptide hormone G protein-coupled receptor (GPCR).…”

Preservation of Glucagon-Like Peptide-1 Level Attenuates Angiotensin II-Induced Tissue Fibrosis by Altering AT1/AT2 Receptor Expression and Angiotensin-Converting Enzyme 2 Activity in Rat Heart

“…Endogenous GLP-1 has a short plasma half-life and is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4) [10]. Liraglutide is a long-acting GLP-1 receptor agonist for the treatment of type 2 diabetes.…”