Abstract
The glucagon-like peptide-1 receptor (GLP-1R) is a G-protein-coupled receptor (GPCR) whose activation results in suppression of food intake and improvement of glucose metabolism. Several receptor interacting proteins regulate the signaling of GLP-1R such as G protein-coupled receptor kinases (GRK) and β-arrestins. Here we evaluated the physiological and pharmacological impact of GRK inhibition on GLP-1R activity leveraging small molecule inhibitors of GRK2 and GRK3. We demonstrated that inhibition of GRK: i) inhibited GLP-1-mediated β-arrestin recruitment, ii) enhanced GLP-1-induced insulin secretion in isolated islets and iii) has additive effect with dipeptidyl peptidase 4 in mediating suppression of glucose excursion in mice. These findings highlight the importance of GRK to modulate GLP-1R function in vitro and in vivo. GRK inhibition is a potential therapeutic approach to enhance endogenous and pharmacologically stimulated GLP-1R signaling.
Highlights
Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are an important therapy for patients with type 2 diabetes (T2D) given their ability to improve glucose metabolism and their associated weight loss, low risk for hypoglycemia and positive effects on cardiovascular outcomes [1, 2]
GLP-1R belongs to the Class B Gprotein-coupled receptors (GPCRs) and GLP-1R stimulation leads to cAMP production, Ca2+ mobilization, and phosphorylation of ERK1/2 [1, 9, 12,13,14]
To confirm that GLP-1 can induce the recruitment of GRK2 and b-arrestin to the GLP-1 receptor we used two small molecule GRK2/3 (GRK) inhibitors (Cpd A and B) with good selectivity and permeability [19]
Summary
Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are an important therapy for patients with type 2 diabetes (T2D) given their ability to improve glucose metabolism and their associated weight loss, low risk for hypoglycemia and positive effects on cardiovascular outcomes [1, 2]. Strategies that activate GLP-1R or stabilize active GLP-1 with pharmacological agonists or with Dipeptidyl Peptidase-4 Inhibitors (DPP-4i), are the subject of an intensive drug discovery effort [1, 9,10,11]. Another potential approach to potentiate and prolongate GLP-1R activation is by inhibiting proteins involved in termination of the receptor signaling. For most GPCRs, homologous desensitization is thought to involve phosphorylation by G protein-coupled receptor kinases that results in recruitment of b-arrestins [15].
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