title: AMP-activated protein kinase as regulator of P2Y(6) receptor-induced insulin secretion in mouse pancreatic β-cells.
abstract: 5'-AMP-activated protein kinase (AMPK) and its pharmacological modulators have been targeted for treating type 2 diabetes. Extracellular uridine 5'-diphosphate (UDP) activates P2Y6 receptors (P2Y6Rs) in pancreatic β-cells to release insulin and reduce apoptosis, which would benefit diabetes. Here, we studied the role of P2Y6R in activation of AMPK in MIN6 mouse pancreatic β-cells and insulin secretion. Treatment with a potent P2Y6R dinucleotide agonist MRS2957 (500nM) activated AMPK, which was blocked by P2Y6R-selective antagonist MRS2578. Also, MRS2957 induced phosphorylation of acetyl-coenzyme A carboxylase (ACC), a marker of AMPK activity. Calcium chelator BAPTA-AM, calmodulin-dependent protein kinase kinase (CaMKK) inhibitor STO-069 and IP3 receptor antagonist 2-APB attenuated P2Y6R-mediated AMPK phosphorylation revealing involvement of intracellular Ca(2+) pathways. P2Y6R agonist induced insulin secretion at high glucose, which was reduced by AMPK siRNA. Thus, P2Y6R has a crucial role in β-cell function, suggesting its potential as a therapeutic target in diabetes.
authors: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0810, USA.
authors: Ramachandran
authors: R
authors: Balasubramanian
authors: Hiroshi
authors: H
authors: Maruoka
authors: P Suresh
authors: PS
authors: Jayasekara
authors: Zhan-Guo
authors: ZG
authors: Gao
authors: Kenneth A
authors: KA
authors: Jacobson
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D058910:Purinergic P2 Receptor Agonists / Q000494:pharmacology; D018048:Receptors, Purinergic P2 / Q000502:physiology*
chemical_list: D007328:Insulin; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; C099845:purinoceptor P2Y6; D055372:AMP-Activated Protein Kinases