title: Identification of a small molecule activator of novel PKCs for promoting glucose-dependent insulin secretion.
abstract: Using an image-based screen for small molecules that can affect Golgi morphology, we identify a small molecule, Sioc145, which can enlarge the Golgi compartments and promote protein secretion. More importantly, Sioc145 potentiates insulin secretion in a glucose-dependent manner. We show that Sioc145 selectively activates novel protein kinase Cs (nPKCs; δ and ɛ) but not conventional PKCs (cPKCs; α, βI and βII) in INS-1E insulinoma cells. In contrast, PMA, a non-selective activator of cPKCs and nPKCs, promotes insulin secretion independent of glucose concentrations. Furthermore, we demonstrate that Sioc145 and PMA show differential abilities in depolarizing the cell membrane, and suggest that Sioc145 promotes insulin secretion in the amplifying pathway downstream of K(ATP) channels. In pancreatic islets, the treatment with Sioc145 enhances the second phase of insulin secretion. Increased insulin granules close to the plasma membrane are observed after Sioc145 treatment. Finally, the administration of Sioc145 to diabetic GK rats increases their serum insulin levels and improves glucose tolerance. Collectively, our studies identify Sioc145 as a novel glucose-dependent insulinotropic compound via selectively activating nPKCs.
authors.affiliation: Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Han
authors.forename: Heling
authors.initials: H
authors.lastname: Pan
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Tan
authors.forename: Dawei
authors.initials: D
authors.lastname: Ma
authors.forename: Junying
authors.initials: J
authors.lastname: Yuan
authors.forename: Jia-Rui
authors.initials: JR
authors.lastname: Wu
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D005947:Glucose / Q000378:metabolism*; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D007340:Insulinoma / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008854:Microscopy, Electron; D015221:Potassium Channels / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D007328:Insulin; D015221:Potassium Channels; C561751:Sioc145 compound; D011493:Protein Kinase C; D005947:Glucose; D002118:Calcium