title: Protein histidine [de]phosphorylation in insulin secretion: abnormalities in models of impaired insulin secretion.
abstract: In the majority of cell types, including the islet β-cell, transduction of extracellular signals involves ligand binding to a receptor, often followed by the activation G proteins and their effector modules. The islet β-cell is unusual in that glucose lacks an extracellular receptor. Instead, events consequent to glucose metabolism promote insulin secretion via the generation of diffusible second messengers and mobilization of calcium. A selective increase in intracellular calcium has been shown to regulate the phosphorylation status key islet proteins thereby facilitating insulin secretion. In addition to classical protein kinases [e.g., protein kinases A and C], recent studies from our laboratory have focused on the expression and function of various forms of NDPK/nm23-like histidine kinases in clonal β-cells, normal rodent, and human islets. Further, we recently reported localization of a cytosolic protein histidine phosphatase [PHP] in INS 832/13 cells, normal rat islets, and human islets. siRNA-mediated knock down of nm23-H1 and PHP in insulin-secreting INS 832/13 cells significantly attenuated glucose-induced insulin secretion. We also observed significant alterations in the expression and function of nm23-H1/PHP in β-cells chronically exposed to elevated levels of glucose and saturated fatty acids, such as palmitate (i.e., glucolipotoxicity). Similar changes were also noted in islets from the Goto-Kakizaki and Zucker Diabetic Fatty rats, two known models for type 2 diabetes. It is concluded that protein histidine phosphorylation-dephosphorylation cycles play novel regulatory roles in G protein-mediated physiological insulin secretion and that abnormalities in this signaling axis lead to impaired insulin secretion in glucolipotoxicity and type 2 diabetes.
authors.affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, John D. Dingell VA Medical Center, Detroit, MI 48201, USA. akowluru@med.wayne.edu
authors.forename: Anjaneyulu
authors.initials: A
authors.lastname: Kowluru
authors.forename: Susanne
authors.initials: S
authors.lastname: Klumpp
authors.forename: Josef
authors.initials: J
authors.lastname: Krieglstein
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006639:Histidine / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000201:enzymology / Q000378:metabolism*; D008954:Models, Biological; D054778:NM23 Nucleoside Diphosphate Kinases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation
chemical_list: D007328:Insulin; D054778:NM23 Nucleoside Diphosphate Kinases; D006639:Histidine; C504019:PHPT1 protein, human; D010744:Phosphoric Monoester Hydrolases