Anchored phosphatases modulate glucose homeostasis.

Imagen de Manuel F Navedo
TítuloAnchored phosphatases modulate glucose homeostasis.
Publication TypeJournal Article
Year of Publication2012
AutoresHinke, SA, Navedo, MF, Ulman, A, Whiting, JL, Nygren, PJ, Tian, G, Jimenez-Caliani, AJ, Langeberg, LK, Cirulli, V, Tengholm, A, Dell'acqua, ML, L Santana, F, Scott, JD
JournalEMBO J
Volume31
Issue20
Pagination3991-4004
Date Published2012 Oct 17
ISSN1460-2075
Palabras claveA Kinase Anchor Proteins, Amino Acid Motifs, Animals, Calcineurin, Calcium Signaling, Cyclic AMP, Glucose, Homeostasis, Insulin, Insulin resistance, Insulinoma, Islets of Langerhans, Liver, Male, Membrane Potentials, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Models, Molecular, Muscle, Skeletal, Pancreatic Neoplasms, Phosphoprotein Phosphatases, Protein Interaction Mapping, Protein Kinases, Second Messenger Systems, Sequence Deletion, Tumor Cells, Cultured
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.

DOI10.1038/emboj.2012.244
Alternate JournalEMBO J.
PubMed ID22940692
PubMed Central IDPMC3474922
Grant ListDK54441 / DK / NIDDK NIH HHS / United States
GM07750 / GM / NIGMS NIH HHS / United States
GM48231 / GM / NIGMS NIH HHS / United States
HL85686 / HL / NHLBI NIH HHS / United States
HL85870 / HL / NHLBI NIH HHS / United States
HL98200 / HL / NHLBI NIH HHS / United States
NS048154 / NS / NINDS NIH HHS / United States
NS40701 / NS / NINDS NIH HHS / United States
R01 GM048231 / GM / NIGMS NIH HHS / United States
R01 HL098200 / HL / NHLBI NIH HHS / United States
R37 GM048231 / GM / NIGMS NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
/ / Howard Hughes Medical Institute / United States