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: T T Zhou, L L Quan, L P Chen, T Du, K X Sun, J C Zhang, L Yu, Y Li, P Wan, L L Chen, B H Jiang, L H Hu, J Chen, X Shen
• Journal: Cell death & disease (Cell Death Dis) Vol. 7 Pg. e2216 (05 05 2016) ISSN: 2041-4889 [Electronic] England
• PMID: 27148689 (Publication Type: Journal Article)

Chemical References

• Calmodulin
• Hypoglycemic Agents
• Kcnb1 protein, mouse
• Phosphoinositide-3 Kinase Inhibitors
• Potassium Channel Blockers
• Pyrimidines
• SP6616
• Shab Potassium Channels
• Small Molecule Libraries
• Thiazoles
• Streptozocin
• Phosphatidylinositol 3-Kinase
• Proto-Oncogene Proteins c-akt
• Protein Kinase C
• Mapk1 protein, mouse
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Animals
• CHO Cells
• Calmodulin (antagonists & inhibitors, genetics, metabolism)
• Cell Line
• Cell Survival (drug effects)
• Cricetulus
• Diabetes Mellitus, Experimental (chemically induced, drug therapy, genetics, pathology)
• Drug Discovery
• Gene Expression Regulation
• Glucose Tolerance Test
• Hypoglycemic Agents (chemistry, pharmacology)
• Insulin-Secreting Cells (drug effects, metabolism, pathology)
• Male
• Mice
• Mice, Transgenic
• Mitogen-Activated Protein Kinase 1 (antagonists & inhibitors, genetics, metabolism)
• Mitogen-Activated Protein Kinase 3 (antagonists & inhibitors, genetics, metabolism)
• Phosphatidylinositol 3-Kinase (genetics, metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Potassium Channel Blockers (chemistry, pharmacology)
• Protein Kinase C (antagonists & inhibitors, genetics, metabolism)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, genetics, metabolism)
• Pyrimidines (chemistry, pharmacology)
• Shab Potassium Channels (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction
• Small Molecule Libraries (chemistry, pharmacology)
• Streptozocin
• Thiazoles (chemistry, pharmacology)