Anchored phosphatases modulate glucose homeostasis

• DOI: 10.1038/emboj.2012.244
• Publication Date: 2012-08-31T14:39:00Z
• Authors: Simon A Hinke; Manuel F Navedo; Allison Ulman; Jennifer L Whiting; Patrick J Nygren; Geng Tian; Antonio J Jimenez...; Lorene K Langeberg; Vincenzo Cirulli; Anders Tengholm; Mark L Dell‧Acqua; L Fernando Santana; John D Scott
• Keywords: Male; 0301 basic medicine; Biomedical and clinical sciences; Medical Physiology; Amino Acid Motifs; A Kinase Anchor Proteins; Inbred C57BL; Second Messenger Systems; Medical and Health Sciences; Membrane Potentials; Mice; Models; Protein Interaction Mapping; Insulin Secretion; Phosphoprotein Phosphatases; Cyclic AMP; 2.1 Biological and endogenous factors; Homeostasis; Insulin; calcineurin; glucose-stimulated insulin secretion; Sequence Deletion; Mice, Knockout; Cultured; Calcineurin; Diabetes; Skeletal; Biological Sciences; Tumor Cells; Biological sciences; Liver; Muscle; 570; A-kinase anchoring protein; 1.1 Normal biological development and functioning; Knockout; 612; cyclic-AMP-dependent protein kinase; Article; Islets of Langerhans; 03 medical and health sciences; Information and Computing Sciences; Animals; Calcium Signaling; Metabolic and endocrine; Biomedical and Clinical Sciences; Molecular; Membrane Proteins; Pancreatic Neoplasms; Mice, Inbred C57BL; Glucose; Insulinoma; Biochemistry and Cell Biology; glucoregulation; Insulin Resistance; Protein Kinases; Developmental Biology

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.