Anchored phosphatases modulate glucose homeostasis

Simon A. Hinke, Manuel F Navedo, Allison Ulman, Jennifer L. Whiting, Patrick J. Nygren, Geng Tian, Antonio J. Jimenez-Caliani, Lorene K. Langeberg, Vincenzo Cirulli, Anders Tengholm, Mark L. Dell'Acqua, Luis Fernando Santana, John D. Scott

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Endocrine release of insulin principally controls glucose homeostasis. Nutrient-induced exocytosis of insulin granules from pancreatic β-cells involves ion channels and mobilization of Ca 2+ and cyclic AMP (cAMP) signalling pathways. Whole-animal physiology, islet studies and live-β-cell imaging approaches reveal that ablation of the kinase/phosphatase anchoring protein AKAP150 impairs insulin secretion in mice. Loss of AKAP150 impacts L-type Ca 2+ currents, and attenuates cytoplasmic accumulation of Ca 2+ and cAMP in β-cells. Yet surprisingly AKAP150 null animals display improved glucose handling and heightened insulin sensitivity in skeletal muscle. More refined analyses of AKAP150 knock-in mice unable to anchor protein kinase A or protein phosphatase 2B uncover an unexpected observation that tethering of phosphatases to a seven-residue sequence of the anchoring protein is the predominant molecular event underlying these metabolic phenotypes. Thus anchored signalling events that facilitate insulin secretion and glucose homeostasis may be set by AKAP150 associated phosphatase activity.

Original languageEnglish (US)
Pages (from-to)3991-4004
Number of pages14
JournalEMBO Journal
Volume31
Issue number20
DOIs
StatePublished - Oct 17 2012
Externally publishedYes

Keywords

  • A-kinase anchoring protein (AKAP)
  • calcineurin (PP2B)
  • cyclic-AMP-dependent protein kinase (PKA)
  • glucoregulation
  • glucose-stimulated insulin secretion (GSIS)

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)

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  • Cite this

    Hinke, S. A., Navedo, M. F., Ulman, A., Whiting, J. L., Nygren, P. J., Tian, G., Jimenez-Caliani, A. J., Langeberg, L. K., Cirulli, V., Tengholm, A., Dell'Acqua, M. L., Santana, L. F., & Scott, J. D. (2012). Anchored phosphatases modulate glucose homeostasis. EMBO Journal, 31(20), 3991-4004. https://doi.org/10.1038/emboj.2012.244