title: Incretin-stimulated interaction between β-cell Kv1.5 and Kvβ2 channel proteins involves acetylation/deacetylation by CBP/SirT1.
abstract: The incretins, GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) are gastrointestinal hormones conferring a number of beneficial effects on β-cell secretion, survival and proliferation. In a previous study, it was demonstrated that delayed rectifier channel protein Kv2.1 contributes to β-cell apoptosis and that the prosurvival effects of incretins involve Kv2.1 PTMs (post-translational modifications), including phosphorylation and acetylation. Since Kv1.5 overexpression was also shown to stimulate β-cell death, the present study was initiated in order to determine whether incretins modulate Kv1.5α-Kvβ2 interaction via PTM and the mechanisms involved. GIP and GLP-1 reduced apoptosis in INS-1 β-cells (clone 832/13) overexpressing Kv1.5, and RNAi (RNA interference)-mediated knockdown of endogenous Kv1.5 attenuated apoptotic β-cell death. Both GIP and GLP-1 increased phosphorylation and acetylation of Kv1.5 and its Kvβ2 protein subunit, leading to their enhanced interaction. Further studies demonstrated that CBP [CREB (cAMP-response-element-binding protein)-binding protein]/SirT1 mediated acetylation/deacetylation and interaction between Kvβ2 and Kv1.5 in response to GIP or GLP-1. Incretin regulation of β-cell function therefore involves the acetylation of multiple Kvα and Kvβ subunits.
authors: Department of Cellular & Physiological Sciences, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada.
authors: Su-Jin
authors: SJ
authors: Kim
authors: Ziliang
authors: Z
authors: Ao
authors: Garth
authors: G
authors: Warnock
authors: Christopher H S
authors: CH
authors: McIntosh
mesh_terms: D000107:Acetylation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D054795:Incretins / Q000378:metabolism / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051666:Kv1.5 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D051637:Shaker Superfamily of Potassium Channels; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: D054795:Incretins; C496981:KCNA5 protein, human; C498948:KCNAB2 protein, human; D051666:Kv1.5 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; D051637:Shaker Superfamily of Potassium Channels; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1