Incretin-stimulated interaction between β-cell Kv1.5 and Kvβ2 channel proteins involves acetylation/deacetylation by CBP/SirT1.

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.