Signaling profiles in HEK 293T cells co-expressing GLP-1 and GIP receptors  

作　　者：Yu-zhe Wang De-hua Yang Ming-wei Wang 

机构地区：[1]The National Center for Drug Screening,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [2]University of Chinese Academy of Sciences,Beijing 100049,China [3]The CAS Key Laboratory of Receptor Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [4]Department of Pharmacology,School of Basic Medical Sciences,Fudan University,Shanghai 200032,China

出　　处：《Acta Pharmacologica Sinica》2022年第6期1453-1460,共8页中国药理学报（英文版）

基　　金：This work was partially supported by National Natural Science Foundation of China 81872915(MWW),82073904(MWW),81773792(DHY)and 81973373(DHY);National Science and Technology Major Project of China–Key New Drug Creation and Manufacturing Program 2018ZX09735–001(MWW)and 2018ZX09711002–002–005(DHY);the National Key Basic Research Program of China 2018YFA0507000(MWW);Novo Nordisk-CAS Research Fund grant NNCAS-2017–1-CC(DHY);SA-SIBS Scholarship Program(DHY).

摘　　要：Glucagon-like peptide-1(GLP-1)and glucose-dependent insulinotropic polypeptide(GIP)are regarded as‘incretins’working closely to regulate glucose homeostasis.Unimolecular dual and triple agonists of GLP-1R and GIPR have shown remarkable clinical benefits in treating type 2 diabetes.However,their pharmacological characterization is usually carried out in a single receptor-expressing system.In the present study we constructed a co-expression system of both GLP-1R and GIPR to study the signaling profiles elicited by mono,dual and triple agonists.We show that when the two receptors were co-expressed in HEK 293T cells with comparable receptor ratio to pancreatic cancer cells,GIP predominately induced cAMP accumulation while GLP-1 was biased towardsβ-arrestin 2 recruitment.The presence of GIPR negatively impacted GLP-1R-mediated cAMP andβ-arrestin 2 responses.While sharing some common modulating features,dual agonists(peptide 19 and LY3298176)and a triple agonist displayed differentiated signaling profiles as well as negative impact on the heteromerization that may help interpret their superior clinical efficacies.

关 键 词：glucagon-like peptide-1 receptor glucose-dependent insulinotropic peptide receptor peptide 19 LY3298176 heteromerization type 2 diabetes 

分 类 号：R737.9[医药卫生—肿瘤]