title: Anchored phosphatases modulate glucose homeostasis.
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.
authors.affiliation: Department of Pharmacology, Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Hinke
authors.forename: Manuel F
authors.initials: MF
authors.lastname: Navedo
authors.forename: Allison
authors.initials: A
authors.lastname: Ulman
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Whiting
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Nygren
authors.forename: Geng
authors.initials: G
authors.lastname: Tian
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Jimenez-Caliani
authors.forename: Lorene K
authors.initials: LK
authors.lastname: Langeberg
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cirulli
authors.forename: Anders
authors.initials: A
authors.lastname: Tengholm
authors.forename: Mark L
authors.initials: ML
authors.lastname: Dell'Acqua
authors.forename: L Fernando
authors.initials: LF
authors.lastname: Santana
authors.forename: John D
authors.initials: JD
authors.lastname: Scott
mesh_terms: D054758:A Kinase Anchor Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020816:Amino Acid Motifs; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D000242:Cyclic AMP / Q000502:physiology; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics*; D000078790:Insulin Secretion; D007340:Insulinoma / Q000473:pathology; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008958:Models, Molecular; D018482:Muscle, Skeletal / Q000201:enzymology; D010190:Pancreatic Neoplasms / Q000473:pathology; D010749:Phosphoprotein Phosphatases / Q000502:physiology*; D025941:Protein Interaction Mapping; D011494:Protein Kinases / Q000378:metabolism; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology; D017384:Sequence Deletion; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
chemical_list: D054758:A Kinase Anchor Proteins; C520665:Akap5 protein, mouse; D007328:Insulin; D008565:Membrane Proteins; D000242:Cyclic AMP; D011494:Protein Kinases; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D005947:Glucose