Anchored phosphatases modulate glucose homeostasis

Abstract

Endocrine release of insulin principally controls glucose homeostasis. Nutrient-induced exocytosis of insulin granules from pancreatic b-cells involves ion channels and mobilization of Ca 2 þ and cyclic AMP (cAMP) signalling pathways. Whole-animal physiology, islet studies and live-b-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 þ currents, and attenuates cytoplasmic accumulation of Ca 2 þ and cAMP in b-cells. Yet surprisingly AKAP150 null animals display improved glucose handling and heightened insulin sensitivity in skeletal muscle. More refined analyses of AKAP150 knockin 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.

Local cAMP signaling in disease at a glance

“…Results from mass spectrometry of intact protein complexes and crystal structures of calcineurin-anchoring peptide complexes (Li et al, 2012a;Li et al, 2007) are consistent with the binding of two copies of this phosphatase per AKAP150 polypeptide, although it remains to be established whether this is always the physiological stoichiometry. AKAP150-null mice exhibit impaired insulin secretion with decreases in both glucosestimulated Ca 2+ entry (illustrated in the Diabetes panel) and cAMP production (Hinke et al, 2012). These data are consistent with a central role for AKAP150 in coordinating cAMP signaling in pancreatic b-cells.…”

“…Recently, the contribution of AKAP150 (encoded by Akap5; the human ortholog is also known as AKAP79) to the modulation of glucose homeostasis in mice has been reported (Hinke et al, 2012). This dimeric (Gao et al, 2011;Gold et al, 2011) protein coanchors PKA with multiple signaling components, including AC (Bauman et al, 2006) and the Ca 2+ /CaM-activated protein phosphatase calcineurin (Coghlan et al, 1995) (see Diabetes panel of the poster).…”

A-kinase Anchoring Protein 79/150 Recruits Protein Kinase C to Phosphorylate Roundabout Receptors

“…Protein kinase A-anchoring proteins modulate membrane proximal signaling events, principally by tethering protein kinases and phosphatases in the vicinity of G-protein-coupled receptors, ion channels, and adenylyl cyclases (7,25,(51)(52)(53)(54). Taken together, the data in Fig.…”

Targeted Disruption of the SUCNR1 Metabolic Receptor Leads to Dichotomous Effects on Obesity

“…Total pancreatic insulin content was measured as described (29). Pancreata were harvested from fed mice, Polytron homogenized (30 s) on ice in 5 mL cold 2 N acetic acid, boiled for 5 min, transferred to ice, and centrifuged at 15,000g and 4°C for 15 min.…”