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

doi:10.1038/s41401-021-00758-6

	Signaling profiles in HEK 293T cells co-expressing GLP-1 and GIP receptors
	Wang, Yu-zhe 1,2; Yang, De-hua 1,2,3; Wang, Ming-wei 1,2,3,4
刊名	ACTA PHARMACOLOGICA SINICA
	2021-08-26
页码	8
关键词	glucagon-like peptide-1 receptor glucose-dependent insulinotropic peptide receptor peptide 19 LY3298176 heteromerization type 2 diabetes
ISSN号	1671-4083
DOI	10.1038/s41401-021-00758-6
通讯作者	Yang, De-hua(dhyang@simm.ac.cn) ; Wang, Ming-wei(mwwang@simm.ac.cn)
英文摘要	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 towards beta-arrestin 2 recruitment. The presence of GIPR negatively impacted GLP-1R-mediated cAMP and beta-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.
资助项目	National Natural Science Foundation of China[81872915] ; National Natural Science Foundation of China[82073904] ; National Natural Science Foundation of China[81773792] ; National Natural Science Foundation of China[81973373] ; National Science and Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2018ZX09735-001] ; National Science and Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2018ZX09711002-002-005] ; National Key Basic Research Program of China[2018YFA0507000] ; Novo Nordisk-CAS Research Fund[NNCAS-2017-1-CC] ; SA-SIBS Scholarship Program
WOS关键词	GLUCAGON-LIKE PEPTIDE-1 ; GLUCOSE-INTOLERANCE ; SECRETION ; INCRETINS ; OBESITY
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000689541100001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/297771]
专题	中国科学院上海药物研究所
通讯作者	Yang, De-hua; Wang, Ming-wei
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 4.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai 200032, Peoples R China
推荐引用方式 GB/T 7714	Wang, Yu-zhe,Yang, De-hua,Wang, Ming-wei. Signaling profiles in HEK 293T cells co-expressing GLP-1 and GIP receptors[J]. ACTA PHARMACOLOGICA SINICA,2021:8.
APA	Wang, Yu-zhe,Yang, De-hua,&Wang, Ming-wei.(2021).Signaling profiles in HEK 293T cells co-expressing GLP-1 and GIP receptors.ACTA PHARMACOLOGICA SINICA,8.
MLA	Wang, Yu-zhe,et al."Signaling profiles in HEK 293T cells co-expressing GLP-1 and GIP receptors".ACTA PHARMACOLOGICA SINICA (2021):8.