SP6616 as a new Kv2.1 channel inhibitor efficiently promotes beta-cell survival involving both PKC/Erk1/2 and CaM/PI3K/Akt signaling pathways

doi:10.1038/cddis.2016.119

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药物安全性评价中心

	SP6616 as a new Kv2.1 channel inhibitor efficiently promotes beta-cell survival involving both PKC/Erk1/2 and CaM/PI3K/Akt signaling pathways
	Zhou, T. T.1,2; Quan, L. L.3; Chen, L. P.1,2; Du, T.1,2; Sun, K. X.1; Zhang, J. C.3; Yu, L.1,2 ; Li, Y.1,2 ; Wan, P.3; Chen, L. L.1,2
刊名	CELL DEATH & DISEASE
	2016-05
卷号	7
ISSN号	2041-4889
DOI	10.1038/cddis.2016.119
文献子类	Article
英文摘要	Kv2.1 as a voltage-gated potassium (Kv) channel subunit has a pivotal role in the regulation of glucose-stimulated insulin secretion (GSIS) and pancreatic beta-cell apoptosis, and is believed to be a promising target for anti-diabetic drug discovery, although the mechanism underlying the Kv2.1-mediated beta-cell apoptosis is obscure. Here, the small molecular compound, ethyl 5-(3-ethoxy-4-methoxyphenyl)-2-(4-hydroxy-3-methoxybenzylidene)-7-methyl-3-oxo-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxylate (SP6616) was discovered to be a new Kv2.1 inhibitor. It was effective in both promoting GSIS and protecting beta cells from apoptosis. Evaluation of SP6616 on either high-fat diet combined with streptozocin-induced type 2 diabetic mice or db/db mice further verified its efficacy in the amelioration of beta-cell dysfunction and glucose homeostasis. SP6616 treatment efficiently increased serum insulin level, restored beta-cell mass, decreased fasting blood glucose and glycated hemoglobin levels, and improved oral glucose tolerance. Mechanism study indicated that the promotion of SP6616 on beta-cell survival was tightly linked to its regulation against both protein kinases C (PKC)/extracellular-regulated protein kinases 1/2 (Erk1/2) and calmodulin(CaM)/phosphatidylinositol 3-kinase(PI3K)/serine/threonine-specific protein kinase (Akt) signaling pathways. To our knowledge, this may be the first report on the underlying pathway responsible for the Kv2.1-mediated beta-cell protection. In addition, our study has also highlighted the potential of SP6616 in the treatment of type 2 diabetes.
资助项目	Chinese National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program"[2014ZX09301-306-003] ; National Natural Science Foundation of China[81373461/81473141/81561148011] ; project of Chinese Academy of Sciences Institute of Pharmaceutical Innovation[CASIMM0120154035]
WOS关键词	DEPENDENT POTASSIUM CHANNELS ; KINASE-C ISOFORMS ; INSULIN-SECRETION ; ION CHANNELS ; GLUCOSE-HOMEOSTASIS ; TARANTULA TOXINS ; HEPG2 CELLS ; K+ CHANNELS ; APOPTOSIS ; ACTIVATION
WOS研究方向	Cell Biology
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000376430400011
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276054]
专题	药物安全性评价中心
通讯作者	Hu, L. H.; Chen, J.; Shen, X.
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Pharmacol 3, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China; 3.Shanghai Normal Univ, Coll Life & Environm Sci, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Zhou, T. T.,Quan, L. L.,Chen, L. P.,et al. SP6616 as a new Kv2.1 channel inhibitor efficiently promotes beta-cell survival involving both PKC/Erk1/2 and CaM/PI3K/Akt signaling pathways[J]. CELL DEATH & DISEASE,2016,7.
APA	Zhou, T. T..,Quan, L. L..,Chen, L. P..,Du, T..,Sun, K. X..,...&Shen, X..(2016).SP6616 as a new Kv2.1 channel inhibitor efficiently promotes beta-cell survival involving both PKC/Erk1/2 and CaM/PI3K/Akt signaling pathways.CELL DEATH & DISEASE,7.
MLA	Zhou, T. T.,et al."SP6616 as a new Kv2.1 channel inhibitor efficiently promotes beta-cell survival involving both PKC/Erk1/2 and CaM/PI3K/Akt signaling pathways".CELL DEATH & DISEASE 7(2016).