title: SP6616 as a new Kv2.1 channel inhibitor efficiently promotes β-cell survival involving both PKC/Erk1/2 and CaM/PI3K/Akt signaling pathways.
abstract: 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 β-cell apoptosis, and is believed to be a promising target for anti-diabetic drug discovery, although the mechanism underlying the Kv2.1-mediated β-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 β 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 β-cell dysfunction and glucose homeostasis. SP6616 treatment efficiently increased serum insulin level, restored β-cell mass, decreased fasting blood glucose and glycated hemoglobin levels, and improved oral glucose tolerance. Mechanism study indicated that the promotion of SP6616 on β-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 β-cell protection. In addition, our study has also highlighted the potential of SP6616 in the treatment of type 2 diabetes.
authors.affiliation: CAS Key Laboratory of Receptor Research, 3th Department of Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: T T
authors.initials: TT
authors.lastname: Zhou
authors.affiliation: College of Life and Environmental Sciences, Shanghai Normal University, Shanghai, China.
authors.forename: L L
authors.initials: LL
authors.lastname: Quan
authors.affiliation: CAS Key Laboratory of Receptor Research, 3th Department of Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: L P
authors.initials: LP
authors.lastname: Chen
authors.affiliation: CAS Key Laboratory of Receptor Research, 3th Department of Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: T
authors.initials: T
authors.lastname: Du
authors.affiliation: CAS Key Laboratory of Receptor Research, 3th Department of Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: K X
authors.initials: KX
authors.lastname: Sun
authors.affiliation: College of Life and Environmental Sciences, Shanghai Normal University, Shanghai, China.
authors.forename: J C
authors.initials: JC
authors.lastname: Zhang
authors.affiliation: CAS Key Laboratory of Receptor Research, 3th Department of Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Yu
authors.affiliation: CAS Key Laboratory of Receptor Research, 3th Department of Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Y
authors.identifier: 0000-0001-7182-6756
authors.initials: Y
authors.lastname: Li
authors.affiliation: College of Life and Environmental Sciences, Shanghai Normal University, Shanghai, China.
authors.forename: P
authors.initials: P
authors.lastname: Wan
authors.affiliation: CAS Key Laboratory of Receptor Research, 3th Department of Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: L L
authors.initials: LL
authors.lastname: Chen
authors.affiliation: CAS Key Laboratory of Receptor Research, 3th Department of Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: B H
authors.initials: BH
authors.lastname: Jiang
authors.affiliation: CAS Key Laboratory of Receptor Research, 3th Department of Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: L H
authors.initials: LH
authors.lastname: Hu
authors.affiliation: CAS Key Laboratory of Receptor Research, 3th Department of Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: CAS Key Laboratory of Receptor Research, 3th Department of Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Shen
mesh_terms: D000818:Animals; D016466:CHO Cells; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003412:Cricetulus; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D055808:Drug Discovery; D005786:Gene Expression Regulation; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D051669:Shab Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013311:Streptozocin; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002147:Calmodulin; D007004:Hypoglycemic Agents; C496990:Kcnb1 protein, mouse; D000081082:Phosphoinositide-3 Kinase Inhibitors; D026902:Potassium Channel Blockers; D011743:Pyrimidines; C000624315:SP6616; D051669:Shab Potassium Channels; D054852:Small Molecule Libraries; D013844:Thiazoles; D013311:Streptozocin; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3