GLP-1 and GIP receptors signal through distinct 0-arrestin 2-dependent pathways to regulate pancreatic 0 cell function

被引：13

作者：

Zaimia, Nour ^{[1
]}

Obeid, Joelle ^{[1
]}

Varrault, Annie ^{[1
]}

Sabatier, Julia ^{[2
]}

Broca, Christophe ^{[2
]}

Gilon, Patrick ^{[3
]}

Costes, Safia ^{[1
]}

Bertrand, Gyslaine ^{[1
]}

Ravier, Magalie A. ^{[1
]}

机构：

[1] Univ Montpellier, IGF, CNRS, INSERM, Montpellier, France

[2] CHU Montpellier, LTCD, IRMB, Montpellier, France

[3] Catholic Univ Louvain, Inst Rech Expt & Clin, Pole Endocrinol Diabet & Nutr, Brussels, Belgium

来源：

CELL REPORTS | 2023年 / 42卷 / 11期

关键词：

INSULIN-SECRETION; DOWN-REGULATION; DELTA CELLS; BETA-CELLS; GLUCAGON; PROTEIN; ARRESTINS; DYNAMICS; KINASE; ALPHA;

D O I：

10.1016/j.celrep.2023.113326

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Glucagon-like peptide 1 (GLP-1R) and glucose-dependent insulinotropic polypeptide (GIPR) receptors are G-protein-coupled receptors involved in glucose homeostasis. Diabetogenic conditions decrease 0-arrestin 2 (ARRB2) levels in human islets. In mouse 0 cells, ARRB2 dampens insulin secretion by partially uncoupling cyclic AMP (cAMP)/protein kinase A (PKA) signaling at physiological doses of GLP-1, whereas at pharmaco-logical doses, the activation of extracellular signal-related kinase (ERK)/cAMP-responsive element-binding protein (CREB) requires ARRB2. In contrast, GIP-potentiated insulin secretion needs ARRB2 in mouse and human islets. The GIPR-ARRB2 axis is not involved in cAMP/PKA or ERK signaling but does mediate GIP -induced F-actin depolymerization. Finally, the dual GLP-1/GIP agonist tirzepatide does not require ARRB2 for the potentiation of insulin secretion. Thus, ARRB2 plays distinct roles in regulating GLP-1R and GIPR signaling, and we highlight (1) its role in the physiological context and the possible functional consequences of its decreased expression in pathological situations such as diabetes and (2) the importance of assessing the signaling pathways engaged by the agonists (biased/dual) for therapeutic purposes.

引用

页数：21