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• W1515082172 abstract "Have you seen?14 September 2012free access Setting sail for glucose homeostasis with the AKAP150-PP2B-anchor Adrian Kee Keong Teo Adrian Kee Keong Teo Section of Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Search for more papers by this author Rohit N Kulkarni Corresponding Author Rohit N Kulkarni Section of Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Search for more papers by this author Adrian Kee Keong Teo Adrian Kee Keong Teo Section of Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Search for more papers by this author Rohit N Kulkarni Corresponding Author Rohit N Kulkarni Section of Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Search for more papers by this author Author Information Adrian Kee Keong Teo1 and Rohit N Kulkarni 1 1Section of Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA *Correspondence to: [email protected] The EMBO Journal (2012)31:3956-3957https://doi.org/10.1038/emboj.2012.265 There is an Article (October 2012) associated with this Have you seen?. PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Glucose-stimulated insulin secretion, controlled by multiple protein phosphorylation events, is critical for the regulation of glucose homeostasis. Protein kinase A (PKA) is known to play a role in β cell physiology, but the role of its anchoring protein is not fully understood. Hinke et al (2012) illustrate the significance of A-kinase anchoring protein 150 in tethering protein phosphatase 2B to mediate nutrient-stimulated insulin secretion and thus modulate glucose homeostasis. Insulin secretion is a key component in the regulation of glucose homeostasis. The initiation of glucose-stimulated insulin secretion (GSIS) is coordinated by numerous protein phosphorylation and dephosphorylation events in the β cell (Jones and Persaud, 1998). PKA and protein phosphatase 2B (PP2B or calcineurin—a Ca2+/calmodulin-dependent enzyme) are examples of enzymes that can influence the release of insulin. The combined effects of these enzymes propagate GSIS, which is mediated intracellularly via an increase in ATP concentration, Ca2+ influx via the voltage-dependent Ca2+ channel (VDCC) and cyclic AMP (cAMP) signalling. At the same time, these enzymes can also regulate glucose usage (e.g., via glycogen synthase) in insulin-sensitive tissues such as the skeletal muscle. cAMP signalling serves to potentiate GSIS via either (1) PKA-dependent or (2) PKA-independent mechanisms (involving cAMP-binding protein Epac2A (exchange protein directly activated by cAMP 2)). A-kinase anchoring protein (AKAP) belongs to a group of regulatory proteins that interacts with cAMP-dependent PKA (Pidoux and Tasken, 2010; Welch et al, 2010). It can regulate the differential usage of kinase versus phosphatase, thereby controlling metabolic outcomes in specific tissues. Although it is known that PKA phosphorylation regulates β cell physiology, the role of such anchoring proteins is less clear (Faruque et al, 2009; Lester et al, 2001). For example, while disruption of the AKAP–PKA interaction has been reported to decrease insulin secretion (Lester et al, 1997), the specific regulatory protein that anchors PKA has yet to be identified. In this study, Hinke et al (2012) sought to identify the specific anchoring protein that tethers PKA, and to elucidate its function. Two AKAP proteins, namely, AKAP150 and AKAP220 were first shortlisted from an overlay assay used to detect RII (regulatory subunit of PKA) binding proteins. Subsequently, only AKAP150 was found to be important for nutrient-stimulated insulin secretion. Mice with a global knockout of AKAP150 (AKAP150KO) exhibited insulin secretory defects. AKAP150 binds to and regulates the phosphorylation-dependent VDCC. Thus, these AKAP150KO mice exhibited decreased basal Ca2+ current and glucose-stimulated Ca2+ influx in isolated β cells. One reason for the decrease in Ca2+ current could be attributed to a mislocation of its binding partner PP2B (discussed below). Glucose-stimulated cAMP fluctuation which is necessary for insulin secretion (Dyachok et al, 2008) was also abolished in AKAP150KO mice. Therefore, AKAP150KO mice exhibit an insulin secretory defect due to multiple impairments including (1) decreased Ca2+ influx and (2) defective cAMP production. Surprisingly, while the authors report that global AKAP150KO mice secrete less insulin, the skeletal muscle, an insulin-sensitive peripheral tissue, exhibited improved blood glucose clearance likely due to increased phosphorylation of IRS-1 and Akt/PKB, and activation of AMPK that resulted in improved insulin sensitivity. On the other hand, β cell-specific AKAP150KO mice secrete less insulin upon glucose stimulation despite increased insulin content in the β cell that occurs as an adaptation to the impaired glucose tolerance. These mice clearly exhibited an impaired glucose tolerance that is due to defective insulin secretion because they do not exhibit an increase in insulin sensitivity. Together, these data indicate that the skeletal muscle selectively adapts to the global absence of AKAP150 to compensate for the decrease in insulin in the body. Notably, AKAP150 is also expressed in the liver but does not exhibit compensatory effects while AKAP150 is not expressed in the adipose tissue. AKAP150 can anchor numerous enzymes with different metabolic activities. For instance, it binds PKA and PP2B, two enzymes with opposing functions, to the cell surface membrane. Hinke et al (2012) further investigated the impact of disrupting specific binding partners of AKAP150. Unexpectedly, AKAP150Δ36 mice that lack residues 705–724 and therefore cannot bind PKA exclusively are effectively metabolically normal. It is thus surprising that the anchoring of PKA to AKAP150 is not necessary for proper insulin release although this interaction is important in other cellular systems (Lu et al, 2008, 2011). AKAP150ΔPIX mice lacking residues 655–661 and thus unable to tether to PP2B at a seven-residue PIxIxIT motif demonstrate the same metabolic phenotype as global AKAP150KO mice. This suggests that AKAP150 is critical for tethering PP2B, and that PP2B is the key molecule necessary for insulin secretion in β cells. PP2B is also a determinant of the metabolic phenotypes such as improved insulin sensitivity and glucose handling upon loss of anchorage of PP2B. Overall, Hinke et al (2012) used complementary in vivo approaches including animal physiology, and in vitro islet culture and live-cell imaging to demonstrate the importance of the kinase/phosphatase anchoring protein AKAP150 in regulating nutrient-stimulated insulin secretion and modulating glucose homeostasis in mice (Figure 1). However, it is likely that there are AKAP150-independent mechanisms regulating insulin secretion since islets from AKAP150KO mice continued to respond to glucose stimulation and secrete insulin in both static and dynamic conditions, albeit at lower levels compared to wild-type mice. Importantly, the authors also identified AKAP150 tethering to PP2B as a key molecular event that regulates insulin secretion and glucose homeostasis (Figure 1). Thus, targeting the AKAP150–PP2B interface and the PIxIxIT motif could be therapeutically useful for increasing insulin sensitivity in patients with diabetes and metabolic syndromes. This could involve designing molecules or chemical compounds to bind the motif and block interaction between AKAP150 and PP2B. In parallel, the safety of systemic blockade of this interaction needs to be ascertained. Alternatively, skeletal muscle-specific AKAP150ΔPIX mice could be generated to determine if the metabolic phenotype is similar to global AKAP150ΔPIX mice. Should this be the case, then localized pharmacological blockade of AKAP150–PP2B interaction could be considered. Figure 1.AKAP150 tethered to PP2B at a seven-residue PIxIxIT motif mediates nutrient-stimulated insulin secretion and glucose homeostasis. Both global AKAP150KO and AKAP150ΔPIX (AKAP150-PP2B binding abolished) mice exhibit insulin secretory defects, enhanced insulin sensitivity in skeletal muscle and overall improved glucose tolerance. This infers the importance of AKAP150-PP2B tethering for glucose homeostasis. ‘Tick’ indicates an increase or improvement. ‘Cross’ indicates a defect or impairment. ‘Equal sign’ indicates no change or no effect. Questions emerging from this study are highlighted in red. Download figure Download PowerPoint Several issues worth pursuing include (1) determining the differential adaptive response of the skeletal muscle versus the liver to alterations in insulin sensitivity in global AKAP150KO mice, (2) further investigating the functional relevance of AKAP150 tethering to PKA (by generating β cell-specific AKAP150Δ36 mice) as there is probably a biological rationale for their interaction, (3) exploring whether AKAP150-related or other proteins are expressed and act in different adipose tissue depots, (4) determining whether AKAP150 acts in a similar manner in ‘human’ skeletal muscle and β cells, and (5) examining if polymorphisms in human genes that encode AKAP150 tethering proteins are linked to disorders of glucose metabolism. Acknowledgements RNK is supported by the NIH RO1 DK 67536 and RO1 DK 55523 and the Harvard Stem Cell Institute. Conflict of Interest The authors declare that they have no conflict of interest. References Dyachok O, Idevall-Hagren O, Sagetorp J, Tian G, Wuttke A, Arrieumerlou C, Akusjarvi G, Gylfe E, Tengholm A (2008) Glucose-induced cyclic AMP oscillations regulate pulsatile insulin secretion. Cell Metab 8: 26–37CrossrefCASPubMedWeb of Science®Google Scholar Faruque OM, Le-Nguyen D, Lajoix AD, Vives E, Petit P, Bataille D, Hani EH (2009) Cell-permeable peptide-based disruption of endogenous PKA-AKAP complexes: a tool for studying the molecular roles of AKAP-mediated PKA subcellular anchoring. Am J Physiol Cell Physiol 296: C306–C316CrossrefCASPubMedWeb of Science®Google Scholar Hinke SA, Navedo MF, Ulman A, Whiting JL, Nygren PJ, Tian G, Jimenez-Caliani AJ, Langeberg LK, Cirulli V, Tengholm A, Dell'Acqua ML, Santana LF, Scott JD (2012) Anchored phosphatases modulate glucose homeostasis. EMBO J 31: 3991–4004Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Jones PM, Persaud SJ (1998) Protein kinases, protein phosphorylation, and the regulation of insulin secretion from pancreatic beta-cells. Endocr Rev 19: 429–461CrossrefCASPubMedWeb of Science®Google Scholar Lester LB, Faux MC, Nauert JB, Scott JD (2001) Targeted protein kinase A and PP-2B regulate insulin secretion through reversible phosphorylation. Endocrinology 142: 1218–1227CrossrefCASPubMedWeb of Science®Google Scholar Lester LB, Langeberg LK, Scott JD (1997) Anchoring of protein kinase A facilitates hormone-mediated insulin secretion. Proc Natl Acad Sci USA 94: 14942–14947CrossrefCASPubMedWeb of Science®Google Scholar Lu Y, Zha XM, Kim EY, Schachtele S, Dailey ME, Hall DD, Strack S, Green SH, Hoffman DA, Hell JW (2011) A kinase anchor protein 150 (AKAP150)-associated protein kinase A limits dendritic spine density. J Biol Chem 286: 26496–26506CrossrefCASPubMedWeb of Science®Google Scholar Lu Y, Zhang M, Lim IA, Hall DD, Allen M, Medvedeva Y, McKnight GS, Usachev YM, Hell JW (2008) AKAP150-anchored PKA activity is important for LTD during its induction phase. J Physiol 586: 4155–4164Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Pidoux G, Tasken K (2010) Specificity and spatial dynamics of protein kinase A signaling organized by A-kinase-anchoring proteins. J Mol Endocrinol 44: 271–284CrossrefCASPubMedWeb of Science®Google Scholar Welch EJ, Jones BW, Scott JD (2010) Networking with AKAPs: context-dependent regulation of anchored enzymes. Mol Interv 10: 86–97CrossrefCASPubMedWeb of Science®Google Scholar Previous ArticleNext Article Read MoreAbout the coverClose modalView large imageVolume 31,Issue 20,October 17, 2012Cover image: Giant proteo-liposomes of pulmonary surfactant, material that lines the alveoli of mammals and allows breathing. Each vesicle is 20-50µm in diameter and contains fluorescent dyes highlighting the preferred localization and packing properties of the surfactant lipids and proteins in the membrane. The image was created by Jorge Bernardino de la Serna, who acquired his background in membrane biophysics at the MEMPHYS Center for Biomembrane Physics, Odense, Denmark. Currently, he is a postdoctoral scientist at the University of Oxford, interested in solving immunological questions at the molecular level employing super-resolution microscopy. Volume 31Issue 2017 October 2012In this issue FiguresReferencesRelatedDetailsLoading ..." @default.
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