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Pancreatic β-cell prosurvival effects of the incretin hormones involve post-translational modification of Kv2.1

S-J Kim1, S B Widenmaier, W S Choi

  • 1Departments of Cellular & Physiological Sciences and the Diabetes Research Group, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, Canada.

Cell Death and Differentiation
|August 6, 2011
PubMed

Insights

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) protect pancreatic beta-cells from apoptosis by modifying Kv2.1 channels. These incretin hormones regulate Kv2.1 through phosphorylation and acetylation, enhancing beta-cell survival.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cell Biology

Background:

  • Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are key incretin hormones regulating glucose homeostasis.
  • Incretins exert insulinotropic and anti-apoptotic effects on pancreatic beta-cells, partly through modulation of voltage-gated potassium (Kv) channels.
  • Kv channel activity is linked to cell volume changes during apoptosis, suggesting a role in beta-cell survival.

Purpose of the Study:

  • To investigate if Kv channel regulation contributes to the prosurvival effects of GIP and GLP-1 in pancreatic beta-cells.
  • To identify the specific Kv channel subtype involved and the molecular mechanisms underlying incretin-mediated protection.

Main Methods:

  • Overexpression of Kv2.1 in INS-1 beta-cells to assess its role in apoptosis.
  • Co-stimulation with GIP/GLP-1 to observe effects on apoptosis and Kv2.1 activity.
  • Analysis of Kv2.1 post-translational modifications (phosphorylation and acetylation) using pathways involving PKA/MSK-1 and HAT/HDAC.
  • Investigation of CREB binding protein (CBP) shuttling and interaction with Kv2.1.

Main Results:

  • Overexpression of Kv2.1 potentiated apoptosis under stress, but GIP/GLP-1 co-stimulation suppressed this potentiation.
  • Incretins induced Kv2.1 phosphorylation via PKA/MSK-1 and acetylation via HAT/HDAC.
  • Acetylation of Kv2.1 was mediated by incretin-induced nuclear/cytoplasmic shuttling of CBP.
  • These findings demonstrate a novel role for Kv channel modulation in incretin-mediated beta-cell survival.

Conclusions:

  • Regulation of beta-cell survival by GIP and GLP-1 involves post-translational modifications of Kv2.1 channels.
  • The PKA/MSK-1 and HAT/HDAC pathways, along with CBP, are crucial for incretin-mediated Kv2.1 regulation and beta-cell protection.
  • This study reveals a new mechanism where GPCR signaling influences nuclear export of a lysine acetyltransferase to regulate ion channel function and promote cell survival.

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