Pharmacological Approaches for Delineating Functions of AKAP-Based Signalling Complexes and Finding Therapeutic Targets

  • Katharina Schrade
  • Enno Klussmann
Part of the Cardiac and Vascular Biology book series (Abbreviated title: Card. vasc. biol.)


A-kinase anchoring proteins (AKAPs) comprise a family of scaffolding proteins that direct their interacting partners to defined cellular compartments. The interacting partners can comprise all proteins of canonical cAMP signalling: protein kinase A (PKA), PKA substrates, adenylyl cyclases, phosphodiesterases (PDEs) and protein phosphatases. AKAPs are central for compartmentalising these components and thus for achieving specificity of cAMP signalling cascades. Since AKAPs can additionally bind proteins of other signalling cascades, they constitute nodes for the integration of cellular signalling. Although general functions have been ascribed to several AKAPs, a detailed understanding of the roles of most of their individual protein-protein interactions is lacking. In particular, knowledge of the functions of individual AKAP-PKA interactions is scarce, as they are mediated by conserved domains and difficult to disrupt selectively. In this article, we will discuss pharmacological agents for interference with individual protein-protein interactions of AKAPs. We will mainly focus on recent progress in targeting AKAP-PKA interactions. Since AKAP-directed signalling is dysregulated in some diseases, such agents may be suitable for validating AKAPs as potential drug targets.


A-kinase anchoring proteins PKA Protein kinase A Compartmentalisation cAMP 



Adenylyl cyclase


A-kinase anchoring protein


A-kinase-binding domain

D/D domain

Docking/dimerisation domain of PKA


Exchange proteins directly activated by cAMP




cAMP-dependent protein kinase A


Stapled anchoring disruptor



This work was supported by grants from the Else Kröner-Fresenius-Stiftung (2013_A145), the German-Israeli Foundation (G.I.F. I-1210-286.13/2012), the German Centre for Cardiovascular Research (DZHK 81X210012) and the Deutsche Forschungsgemeinschaft (DFG KL1415/7-1) to E. K.

Compliance with Ethical Standards

Conflict of Interest Statement

The authors declare that they have no conflict of interest.


  1. Acin-Perez R, Salazar E, Kamenetsky M, Buck J, Levin LR, Manfredi G (2009) Cyclic AMP produced inside mitochondria regulates oxidative phosphorylation. Cell Metab 9:265–276. doi: 10.1016/j.cmet.2009.01.012 PubMedPubMedCentralCrossRefGoogle Scholar
  2. Ahmad F, Shen W, Vandeput F, Szabo-Fresnais N, Krall J, Degerman E, Goetz F, Klussmann E, Movsesian M, Manganiello V (2015) Regulation of sarcoplasmic reticulum Ca2+ ATPase 2 (SERCA2) activity by phosphodiesterase 3A (PDE3A) in human myocardium: phosphorylation-dependent interaction of PDE3A1 with SERCA2. J Biol Chem 290:6763–6776. doi: 10.1074/jbc.M115.638585 PubMedPubMedCentralCrossRefGoogle Scholar
  3. Alto NM, Soderling SH, Hoshi N, Langeberg LK, Fayos R, Jennings PA, Scott JD (2003) Bioinformatic design of A-kinase anchoring protein-in silico: a potent and selective peptide antagonist of type II protein kinase A anchoring. Proc Natl Acad Sci U S A 100:4445. doi: 10.1073/pnas.0330734100 PubMedPubMedCentralCrossRefGoogle Scholar
  4. Appert-Collin A, Cotecchia S, Nenniger-Tosato M, Pedrazzini T, Diviani D (2007) The A-kinase anchoring protein (AKAP)-Lbc-signaling complex mediates α1 adrenergic receptor-induced cardiomyocyte hypertrophy. Proc Natl Acad Sci U S A 104:10140–10145. doi: 10.1073/pnas.0701099104 PubMedPubMedCentralCrossRefGoogle Scholar
  5. Aye TT, Soni S, van Veen TAB, van der Heyden MAG, Cappadona S, Varro A, de Weger RA, de Jonge N, Vos MA, Heck AJR, Scholten A (2012) Reorganized PKA-AKAP associations in the failing human heart. J Mol Cell Cardiol 52:511–518. doi: 10.1016/j.yjmcc.2011.06.003 PubMedCrossRefGoogle Scholar
  6. Baillie GS, Huston E, Scotland G, Hodgkin M, Gall I, Peden AH, MacKenzie C, Houslay ES, Currie R, Pettitt TR, Walmsley AR, Wakelam MJO, Warwicker J, Houslay MD (2002) TAPAS-1, a novel microdomain within the unique N-terminal region of the PDE4A1 cAMP-specific phosphodiesterase that allows rapid, Ca2+-triggered membrane association with selectivity for interaction with phosphatidic acid. J Biol Chem 277:28298–28309. doi: 10.1074/jbc.M108353200 PubMedCrossRefGoogle Scholar
  7. Banky P, Roy M, Newlon MG, Morikis D, Haste NM, Taylor SS, Jennings PA (2003) Related protein–protein interaction modules present drastically different surface topographies despite a conserved helical platform. J Mol Biol 330:1117–1129. doi: 10.1016/S0022-2836(03)00552-7 PubMedCrossRefGoogle Scholar
  8. Bechara C, Sagan S (2013) Cell-penetrating peptides: 20 years later, where do we stand? FEBS Lett 587:1693–1702. doi: 10.1016/j.febslet.2013.04.031 PubMedCrossRefGoogle Scholar
  9. Bender AT, Beavo JA (2006) Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev 58:488–520. doi: 10.1124/pr.58.3.5 PubMedCrossRefGoogle Scholar
  10. Berrera M, Dodoni G, Monterisi S, Pertegato V, Zamparo I, Zaccolo M (2008) A toolkit for real-time detection of cAMP: insights into compartmentalized signaling. Handb Exp Pharmacol 186:285–298. doi: 10.1007/978-3-540-72843-6_12 CrossRefGoogle Scholar
  11. Biel M, Michalakis S (2009) Cyclic nucleotide-gated channels. Handb Exp Pharmacol 191:111–136. doi: 10.1007/978-3-540-68964-5_7 CrossRefGoogle Scholar
  12. Bodor GS, Oakeley AE, Allen PD, Crimmins DL, Ladenson JH, Anderson PA (1997) Troponin I phosphorylation in the normal and failing adult human heart. Circulation 96:1495–1500PubMedCrossRefGoogle Scholar
  13. Brooks H, Lebleu B, Vivès E (2005) Tat peptide-mediated cellular delivery: back to basics. Adv Drug Deliv Rev 57:559–577. doi: 10.1016/j.addr.2004.12.001 PubMedCrossRefGoogle Scholar
  14. Burgers PP, Ma Y, Margarucci L, Mackey M, van der Heyden MAG, Ellisman M, Scholten A, Taylor SS, Heck AJR (2012) A small novel A-kinase anchoring protein (AKAP) that localizes specifically protein kinase A-regulatory subunit I (PKA-RI) to the plasma membrane. J Biol Chem 287:43789–43797. doi: 10.1074/jbc.M112.395970 PubMedPubMedCentralCrossRefGoogle Scholar
  15. Burgers PP, Bruystens J, Burnley RJ, Nikolaev VO, Keshwani M, Wu J, Janssen BJC, Taylor SS, Heck AJR, Scholten A (2016) Structure of smAKAP and its regulation by PKA-mediated phosphorylation. FEBS J 283(11):2132–2148. doi: 10.1111/febs.13726 PubMedPubMedCentralCrossRefGoogle Scholar
  16. Burns-Hamuro LL, Ma Y, Kammerer S, Reineke U, Self C, Cook C, Olson GL, Cantor CR, Braun A, Taylor SS (2003) Designing isoform-specific peptide disruptors of protein kinase A localization. Proc Natl Acad Sci 100:4072–4077. doi: 10.1073/pnas.2628038100 PubMedPubMedCentralCrossRefGoogle Scholar
  17. Burzicki G, Voisin-Chiret AS, Sopkovà-de Oliveira Santos J, Rault S (2009) Synthesis of dihalo bi- and terpyridines by regioselective Suzuki–Miyaura cross-coupling reactions. Tetrahedron 65:5413–5417. doi: 10.1016/j.tet.2009.04.049 CrossRefGoogle Scholar
  18. Cadd G, Stanley McKnight G (1989) Distinct patterns of cAMP-dependent protein kinase gene expression in mouse brain. Neuron 3:71–79. doi: 10.1016/0896-6273(89)90116-5 PubMedCrossRefGoogle Scholar
  19. Cadd GG, Uhler MD, McKnight GS (1990) Holoenzymes of cAMP-dependent protein kinase containing the neural form of type I regulatory subunit have an increased sensitivity to cyclic nucleotides. J Biol Chem 265:19502–19506PubMedGoogle Scholar
  20. Cann M (2004) Bicarbonate stimulated adenylyl cyclases. IUBMB Life 56:529–534. doi: 10.1080/15216540400013861 PubMedCrossRefGoogle Scholar
  21. Carlisle Michel JJ, Dodge KL, Wong W, Mayer NC, Langeberg LK, Scott JD (2004) PKA-phosphorylation of PDE4D3 facilitates recruitment of the mAKAP signalling complex. Biochem J 381:587–592. doi: 10.1042/BJ20040846 PubMedPubMedCentralCrossRefGoogle Scholar
  22. Carlson CR, Ruppelt A, Taskén K (2003) A kinase anchoring protein (AKAP) interaction and dimerization of the RIα and RIβ regulatory subunits of protein kinase A in vivo by the yeast two hybrid system. J Mol Biol 327:609–618. doi: 10.1016/S0022-2836(03)00093-7 PubMedCrossRefGoogle Scholar
  23. Carlson CR, Lygren B, Berge T, Hoshi N, Wong W, Taskén K, Scott JD (2006) Delineation of type I protein kinase A-selective signaling events using an RI anchoring disruptor. J Biol Chem 281:21535–21545. doi: 10.1074/jbc.M603223200 PubMedCrossRefGoogle Scholar
  24. Carnegie GK, Burmeister BT (2011) A-kinase anchoring proteins that regulate cardiac remodeling. J Cardiovasc Pharmacol 58:451–458. doi: 10.1097/FJC.0b013e31821c0220 PubMedPubMedCentralCrossRefGoogle Scholar
  25. Carnegie GK, Soughayer J, Smith FD, Pedroja BS, Zhang F, Diviani D, Bristow MR, Kunkel MT, Newton AC, Langeberg LK, Scott JD (2008) AKAP-Lbc mobilizes a cardiac hypertrophy signaling pathway. Mol Cell 32:169–179. doi: 10.1016/j.molcel.2008.08.030 PubMedPubMedCentralCrossRefGoogle Scholar
  26. Carr DW, Stofko-Hahn RE, Fraser ID, Bishop SM, Acott TS, Brennan RG, Scott JD (1991) Interaction of the regulatory subunit (RII) of cAMP-dependent protein kinase with RII-anchoring proteins occurs through an amphipathic helix binding motif. J Biol Chem 266:14188–14192PubMedGoogle Scholar
  27. Carr DW, Stofko-Hahn RE, Fraser ID, Cone RD, Scott JD (1992) Localization of the cAMP-dependent protein kinase to the postsynaptic densities by A-kinase anchoring proteins. Characterization of AKAP 79. J Biol Chem 267:16816–16823PubMedGoogle Scholar
  28. Chang YS, Graves B, Guerlavais V, Tovar C, Packman K, To KH, Olson KA, Kesavan K, Gangurde P, Mukherjee A, Baker T, Darlak K, Elkin C, Filipovic Z, Qureshi FZ, Cai H, Berry P, Feyfant E, Shi XE, Horstick J, Annis DA, Manning AM, Fotouhi N, Nash H, Vassilev LT, Sawyer TK (2013) Stapled α−helical peptide drug development: a potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy. Proc Natl Acad Sci U S A 110:E3445. doi: 10.1073/pnas.1303002110 PubMedPubMedCentralCrossRefGoogle Scholar
  29. Chen Q, Lin RY, Rubin CS (1997) Organelle-specific targeting of protein kinase AII (PKAII). Molecular and in situ characterization of murine A kinase anchor proteins that recruit regulatory subunits of PKAII to the cytoplasmic surface of mitochondria. J Biol Chem 272:15247–15257PubMedCrossRefGoogle Scholar
  30. Christian F, Szaszák M, Friedl S, Drewianka S, Lorenz D, Goncalves A, Furkert J, Vargas C, Schmieder P, Götz F, Zühlke K, Moutty M, Göttert H, Joshi M, Reif B, Haase H, Morano I, Grossmann S, Klukovits A, Verli J, Gáspár R, Noack C, Bergmann M, Kass R, Hampel K, Kashin D, Genieser H-G, Herberg FW, Willoughby D, Cooper DMF, Baillie GS, Houslay MD, von Kries JP, Zimmermann B, Rosenthal W, Klussmann E (2011) Small molecule AKAP-protein kinase A (PKA) interaction disruptors that activate PKA interfere with compartmentalized cAMP signaling in cardiac myocytes. J Biol Chem 286:9079. doi: 10.1074/jbc.M110.160614 PubMedCrossRefGoogle Scholar
  31. Chu Q, Moellering RE, Hilinski GJ, Kim YW, Grossmann TN, Yeh JTH, Verdine GL (2015) Towards understanding cell penetration by stapled peptides. Med Chem Comm 6:111–119. doi: 10.1039/C4MD00131A CrossRefGoogle Scholar
  32. Clackson T, Wells JA (1995) A hot spot of binding energy in a hormone-receptor interface. Science 267:383–386. doi: 10.1126/science.7529940 PubMedCrossRefGoogle Scholar
  33. Clegg CH, Cadd GG, McKnight GS (1988) Genetic characterization of a brain-specific form of the type I regulatory subunit of cAMP-dependent protein kinase. Proc Natl Acad Sci U S A 85:3703PubMedPubMedCentralCrossRefGoogle Scholar
  34. Coghlan VM, Perrino BA, Howard M, Langeberg LK, Hicks JB, Gallatin WM, Scott JD (1995) Association of protein kinase A and protein phosphatase 2B with a common anchoring protein. Science 267:108–111PubMedCrossRefGoogle Scholar
  35. Colson BA, Patel JR, Chen PP, Bekyarova T, Abdalla MI, Tong CW, Fitzsimons DP, Irving TC, Moss RL (2012) Myosin binding protein-C phosphorylation is the principal mediator of protein kinase A effects on thick filament structure in myocardium. J Mol Cell Cardiol 53:609–616. doi: 10.1016/j.yjmcc.2012.07.012 PubMedPubMedCentralCrossRefGoogle Scholar
  36. Craik DJ, Fairlie DP, Liras S, Price D (2013) The future of peptide-based drugs. Chem Biol Drug Des 81:136–147. doi: 10.1111/cbdd.12055 PubMedCrossRefGoogle Scholar
  37. Deak VA, Klussmann E (2015) Pharmacological interference with protein-protein interactions of A-kinase anchoring proteins as a strategy for the treatment of disease. Curr Drug Targets 17(10):1147–1171CrossRefGoogle Scholar
  38. Deák VA, Skroblin P, Dittmayer C, Knobeloch KP, Bachmann S, Klussmann E (2016) The A-kinase anchoring protein GSKIP regulates GSK3β activity and controls palatal shelf fusion in mice. J Biol Chem 291:681–690. doi: 10.1074/jbc.M115.701177 PubMedCrossRefGoogle Scholar
  39. Degorce F, Card A, Soh S, Trinquet E, Knapik GP, Xie B (2009) HTRF: a technology tailored for drug discovery—a review of theoretical aspects and recent applications. Curr Chem Genomics 3:22. doi: 10.2174/1875397300903010022 PubMedPubMedCentralCrossRefGoogle Scholar
  40. Dema A, Perets E, Schulz MS, Deák VA, Klussmann E (2015) Pharmacological targeting of AKAP-directed compartmentalized cAMP signalling. Cell Signal 27:2474–2487. doi: 10.1016/j.cellsig.2015.09.008 PubMedCrossRefGoogle Scholar
  41. Dema A, Schröter MF, Perets E, Skroblin P, Moutty MC, Deàk VA, Birchmeier W, Klussmann E (2016) The A-kinase anchoring protein (AKAP) glycogen synthase kinase 3β interaction protein (GSKIP) regulates β-catenin through its interactions with both protein kinase A (PKA) and GSK3β. J Biol Chem 291:19618–19630. doi: 10.1074/jbc.M116.738047 PubMedPubMedCentralCrossRefGoogle Scholar
  42. Derossi D, Joliot AH, Chassaing G, Prochiantz A (1994) The third helix of the Antennapedia homeodomain translocates through biological membranes. J Biol Chem 269:10444–10450PubMedGoogle Scholar
  43. Diviani D, Dodge-Kafka KL, Li J, Kapiloff MS (2011) A-kinase anchoring proteins: scaffolding proteins in the heart. Am J Physiol Heart Circ Physiol 301:H1742–H1753. doi: 10.1152/ajpheart.00569.2011 PubMedPubMedCentralCrossRefGoogle Scholar
  44. Dostmann WRG, Taylor SS (1991) Identifying the molecular switches that determine whether (Rp)-cAMPS functions as an antagonist or an agonist in the activation of cAMP-dependent protein kinase I. Biochemistry (Mosc) 30:8710–8716. doi: 10.1021/bi00099a032 CrossRefGoogle Scholar
  45. Fancy SPJ, Baranzini SE, Zhao C, Yuk DI, Irvine KA, Kaing S, Sanai N, Franklin RJM, Rowitch DH (2009) Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS. Genes Dev 23:1571–1585. doi: 10.1101/gad.1806309 PubMedPubMedCentralCrossRefGoogle Scholar
  46. Faruque OM, Le-Nguyen D, Lajoix A-D, Vives E, Petit P, Bataille D, Hani E-H (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–C316. doi: 10.1152/ajpcell.00216.2008 PubMedCrossRefGoogle Scholar
  47. Fink MA, Zakhary DR, Mackey JA, Desnoyer RW, Apperson-Hansen C, Damron DS, Bond M (2001) AKAP-mediated targeting of protein kinase A regulates contractility in cardiac myocytes. Circ Res 88:291–297. doi: 10.1161/01.RES.88.3.291 PubMedCrossRefGoogle Scholar
  48. Fischer G, Rossmann M, Hyvönen M (2015) Alternative modulation of protein–protein interactions by small molecules. Curr Opin Biotechnol 35:78–85. doi: 10.1016/j.copbio.2015.04.006 PubMedPubMedCentralCrossRefGoogle Scholar
  49. Flaherty BR, Wang Y, Trope EC, Ho TG, Muralidharan V, Kennedy EJ, Peterson DS (2015) The stapled AKAP disruptor peptide STAD-2 displays antimalarial activity through a PKA-independent mechanism. PLoS One 10:e0129239. doi: 10.1371/journal.pone.0129239 PubMedPubMedCentralCrossRefGoogle Scholar
  50. Furusawa M, Ohnishi T, Taira T, Iguchi-Ariga SM, Ariga H (2001) AMY-1, a c-Myc-binding protein, is localized in the mitochondria of sperm by association with S-AKAP84, an anchor protein of cAMP-dependent protein kinase. J Biol Chem 276:36647–36651. doi: 10.1074/jbc.M103885200 PubMedCrossRefGoogle Scholar
  51. Futaki S, Suzuki T, Ohashi W, Yagami T, Tanaka S, Ueda K, Sugiura Y (2001) Arginine-rich peptides an abundant source of membrane-permeable peptides having potential as carriers for intracellular protein delivery. J Biol Chem 276:5836–5840. doi: 10.1074/jbc.M007540200 PubMedCrossRefGoogle Scholar
  52. Gamm DM, Baude EJ, Uhler MD (1996) The major catalytic subunit isoforms of cAMP-dependent protein kinase have distinct biochemical properties in vitro and in vivo. J Biol Chem 271:15736–15742. doi: 10.1074/jbc.271.26.15736 PubMedCrossRefGoogle Scholar
  53. Gloerich M, Bos JL (2010) Epac: defining a new mechanism for cAMP action. Annu Rev Pharmacol Toxicol 50:355–375. doi: 10.1146/annurev.pharmtox.010909.105714 PubMedCrossRefGoogle Scholar
  54. Gold MG, Lygren B, Dokurno P, Hoshi N, McConnachie G, Taskén K, Carlson CR, Scott JD, Barford D (2006) Molecular basis of AKAP specificity for PKA regulatory subunits. Mol Cell 24:383–395. doi: 10.1016/j.molcel.2006.09.006 PubMedCrossRefGoogle Scholar
  55. Gold MG, Fowler DM, Means CK, Pawson CT, Stephany JJ, Langeberg LK, Fields S, Scott JD (2013) Engineering A-kinase anchoring protein (AKAP)-selective regulatory subunits of protein kinase A (PKA) through structure-based phage selection. J Biol Chem 288:17111. doi: 10.1074/jbc.M112.447326 PubMedPubMedCentralCrossRefGoogle Scholar
  56. Gonzalez GA, Montminy MR (1989) Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 59:675–680. doi: 10.1016/0092-8674(89)90013-5 PubMedCrossRefGoogle Scholar
  57. Götz F, Roske Y, Schulz MS, Autenrieth K, Bertinetti D, Faelber K, Zühlke K, Kreuchwig A, Kennedy E, Krause G, Daumke O, Herberg FW, Heinemann U, Klussmann E (2016) AKAP18:PKA-RIIα structure reveals crucial anchor points for recognition of regulatory subunits of PKA. Biochem J 473(13):1881–1894. doi: 10.1042/BCJ20160242 PubMedPubMedCentralCrossRefGoogle Scholar
  58. Gray PC, Scott JD, Catterall WA (1998) Regulation of ion channels by cAMP-dependent protein kinase and A-kinase anchoring proteins. Curr Opin Neurobiol 8:330–334. doi: 10.1016/S0959-4388(98)80057-3 PubMedCrossRefGoogle Scholar
  59. Guo W, Wisniewski JA, Ji H (2014) Hot spot-based design of small-molecule inhibitors for protein–protein interactions. Bioorg Med Chem Lett 24:2546–2554. doi: 10.1016/j.bmcl.2014.03.095 PubMedCrossRefGoogle Scholar
  60. Haghighi K, Bidwell P, Kranias EG (2014) Phospholamban interactome in cardiac contractility and survival: a new vision of an old friend. J Mol Cell Cardiol 77:160–167. doi: 10.1016/j.yjmcc.2014.10.005 PubMedCrossRefGoogle Scholar
  61. Hasenfuss G (1998) Alterations of calcium-regulatory proteins in heart failure. Cardiovasc Res 37:279–289. doi: 10.1016/S0008-6363(97)00277-0 PubMedCrossRefGoogle Scholar
  62. Herberg FW, Maleszka A, Eide T, Vossebein L, Tasken K (2000) Analysis of A-kinase anchoring protein (AKAP) interaction with protein kinase A (PKA) regulatory subunits: PKA isoform specificity in AKAP binding. J Mol Biol 298:329–339. doi: 10.1006/jmbi.2000.3662 PubMedCrossRefGoogle Scholar
  63. Huang LJ, Durick K, Weiner JA, Chun J, Taylor SS (1997a) Identification of a novel protein kinase A anchoring protein that binds both type I and type II regulatory subunits. J Biol Chem 272:8057–8064. doi: 10.1074/jbc.272.12.8057 PubMedCrossRefGoogle Scholar
  64. Huang LJ, Durick K, Weiner JA, Chun J, Taylor SS (1997b) D-AKAP2, a novel protein kinase A anchoring protein with a putative RGS domain. Proc Natl Acad Sci U S A 94:11184PubMedPubMedCentralCrossRefGoogle Scholar
  65. Huang LJ, Wang L, Ma Y, Durick K, Perkins G, Deerinck TJ, Ellisman MH, Taylor SS (1999) NH2-terminal targeting motifs direct dual specificity A-kinase-anchoring protein 1 (D-AKAP1) to either mitochondria or endoplasmic reticulum. J Cell Biol 145:951–959PubMedPubMedCentralCrossRefGoogle Scholar
  66. Huang T, McDonough CB, Abel T (2006) Compartmentalized PKA signaling events are required for synaptic tagging and capture during hippocampal late-phase long-term potentiation. Eur J Cell Biol 85:635. doi: 10.1016/j.ejcb.2006.02.005 PubMedPubMedCentralCrossRefGoogle Scholar
  67. Hulme JT, Lin TWC, Westenbroek RE, Scheuer T, Catterall WA (2003) β-adrenergic regulation requires direct anchoring of PKA to cardiac CaV1.2 channels via a leucine zipper interaction with A kinase-anchoring protein 15. Proc Natl Acad Sci 100:13093–13098. doi: 10.1073/pnas.2135335100 PubMedPubMedCentralCrossRefGoogle Scholar
  68. Hulme JT, Westenbroek RE, Scheuer T, Catterall WA (2006) Phosphorylation of serine 1928 in the distal C-terminal domain of cardiac CaV1.2 channels during beta1-adrenergic regulation. Proc Natl Acad Sci U S A 103:16574–16579. doi: 10.1073/pnas.0607294103 PubMedPubMedCentralCrossRefGoogle Scholar
  69. Hundsrucker C, Klussmann E (2008) Direct AKAP-mediated protein-protein interactions as potential drug targets. Handb Exp Pharmacol 186:483–503Google Scholar
  70. Hundsrucker C, Skroblin P, Christian F, Zenn H-M, Popara V, Joshi M, Eichhorst J, Wiesner B, Herberg FW, Reif B, Rosenthal W, Klussmann E (2010) Glycogen synthase kinase 3β interaction protein functions as an A-kinase anchoring protein. J Biol Chem 285:5507–5521. doi: 10.1074/jbc.M109.047944 PubMedCrossRefGoogle Scholar
  71. Huston E, Gall I, Houslay TM, Houslay MD (2006) Helix-1 of the cAMP-specific phosphodiesterase PDE4A1 regulates its phospholipase-D-dependent redistribution in response to release of Ca2+. J Cell Sci 119:3799–3810. doi: 10.1242/jcs.03106 PubMedCrossRefGoogle Scholar
  72. Ishikawa Y, Iwatsubo K, Tsunematsu T, Okumura S (2005) Genetic manipulation and functional analysis of cAMP signalling in cardiac muscle: implications for a new target of pharmacotherapy. Biochem Soc Trans 33:1337–1340. doi: 10.1042/BST0331337 PubMedCrossRefGoogle Scholar
  73. Jahnsen T, Hedin L, Lohmann SM, Walter U, Richards JS (1986) The neural type II regulatory subunit of cAMP-dependent protein kinase is present and regulated by hormones in the rat ovary. J Biol Chem 261:6637–6639PubMedGoogle Scholar
  74. Jurevicius J, Fischmeister R (1996) cAMP compartmentation is responsible for a local activation of cardiac Ca2+ channels by beta-adrenergic agonists. Proc Natl Acad Sci U S A 93:295–299PubMedPubMedCentralCrossRefGoogle Scholar
  75. Kapiloff MS, Jackson N, Airhart N (2001) mAKAP and the ryanodine receptor are part of a multi-component signaling complex on the cardiomyocyte nuclear envelope. J Cell Sci 114:3167–3176PubMedGoogle Scholar
  76. Kaupp UB, Seifert R (2002) Cyclic nucleotide-gated ion channels. Physiol Rev 82:769–824. doi: 10.1152/physrev.00008.2002 PubMedCrossRefGoogle Scholar
  77. Kawasaki H, Springett GM, Mochizuki N, Toki S, Nakaya M, Matsuda M, Housman DE, Graybiel AM (1998) A family of cAMP-binding proteins that directly activate Rap1. Science 282:2275–2279. doi: 10.1126/science.282.5397.2275 PubMedCrossRefGoogle Scholar
  78. Kinderman FS, Kim C, von Daake S, Ma Y, Pham BQ, Spraggon G, Xuong N-H, Jennings PA, Taylor SS (2006) A novel and dynamic mechanism for AKAP binding to RII isoforms of cAMP-dependent protein kinase. Mol Cell 24:397–408. doi: 10.1016/j.molcel.2006.09.015 PubMedPubMedCentralCrossRefGoogle Scholar
  79. Klussmann E (2016) Protein–protein interactions of PDE4 family members—functions, interactions and therapeutic value. Cell Signal 28:713–718. doi: 10.1016/j.cellsig.2015.10.005 PubMedCrossRefGoogle Scholar
  80. Kovanich D, van der Heyden MAG, Aye TT, van Veen TAB, Heck AJR, Scholten A (2010) Sphingosine kinase interacting protein is an A-kinase anchoring protein specific for type I cAMP-dependent protein kinase. Chembiochem Eur J Chem Biol 11:963–971. doi: 10.1002/cbic.201000058 CrossRefGoogle Scholar
  81. Kranias EG, Bers DM (2007) Calcium and cardiomyopathies. Subcell Biochem 45:523–537PubMedCrossRefGoogle Scholar
  82. Kranias EG, Hajjar RJ (2012) Modulation of cardiac contractility by the phospholamban/SERCA2a regulatome. Circ Res 110:1646–1660. doi: 10.1161/CIRCRESAHA.111.259754 PubMedPubMedCentralCrossRefGoogle Scholar
  83. Kurokawa J, Motoike HK, Rao J, Kass RS (2004) Regulatory actions of the A-kinase anchoring protein Yotiao on a heart potassium channel downstream of PKA phosphorylation. Proc Natl Acad Sci U S A 101:16374–16378. doi: 10.1073/pnas.0405583101 PubMedPubMedCentralCrossRefGoogle Scholar
  84. Lagane B, Garcia-Perez J, Kellenberger E (2013) Modeling the allosteric modulation of CCR5 function by Maraviroc. Drug Discov Today Technol 10:e297–e305. doi: 10.1016/j.ddtec.2012.07.011 PubMedCrossRefGoogle Scholar
  85. Lee DC, Carmichael DF, Krebs EG, McKnight GS (1983) Isolation of a cDNA clone for the type I regulatory subunit of bovine cAMP-dependent protein kinase. Proc Natl Acad Sci U S A 80:3608–3612PubMedPubMedCentralCrossRefGoogle Scholar
  86. Li J, Negro A, Lopez J, Bauman AL, Henson E, Dodge-Kafka K, Kapiloff MS (2010) The mAKAPβ scaffold regulates cardiac myocyte hypertrophy via recruitment of activated calcineurin. J Mol Cell Cardiol 48:387. doi: 10.1016/j.yjmcc.2009.10.023 PubMedCrossRefGoogle Scholar
  87. Li Y, Chen L, Kass RS, Dessauer CW (2012) The A-kinase anchoring protein Yotiao facilitates complex formation between adenylyl cyclase type 9 and the IKs potassium channel in heart. J Biol Chem 287:29815–29824. doi: 10.1074/jbc.M112.380568 PubMedPubMedCentralCrossRefGoogle Scholar
  88. Lin CC, Chou CH, Howng SL, Hsu CY, Hwang CC, Wang C, Hsu CM, Hong YR (2009) GSKIP, an inhibitor of GSK3beta, mediates the N-cadherin/beta-catenin pool in the differentiation of SH-SY5Y cells. J Cell Biochem 108:1325–1336. doi: 10.1002/jcb.22362 PubMedCrossRefGoogle Scholar
  89. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46:3–26PubMedCrossRefGoogle Scholar
  90. Lodish H, Berk A, Zipursky SL, Matsudaira P, Baltimore D, Darnell J (2000) Molecular Cell Biology, 4th edition. Chapter 20.6 Second Messengers. New York: W.H. Freeman. ISBN-10: 0-7167-3136-3Google Scholar
  91. Lygren B, Carlson CR, Santamaria K, Lissandron V, McSorley T, Litzenberg J, Lorenz D, Wiesner B, Rosenthal W, Zaccolo M, Taskén K, Klussmann E (2007) AKAP complex regulates Ca2+ re-uptake into heart sarcoplasmic reticulum. EMBO Rep 8:1061. doi: 10.1038/sj.embor.7401081 PubMedPubMedCentralCrossRefGoogle Scholar
  92. MacLennan DH, Kranias EG (2003) Phospholamban: a crucial regulator of cardiac contractility. Nat Rev Mol Cell Biol 4:566–577. doi: 10.1038/nrm1151 PubMedCrossRefGoogle Scholar
  93. MacLennan DH, Asahi M, Tupling AR (2003) The regulation of SERCA-type pumps by phospholamban and sarcolipin. Ann N Y Acad Sci 986:472–480PubMedCrossRefGoogle Scholar
  94. Makarova KS, Wolf YI, Alkhnbashi OS, Costa F, Shah SA, Saunders SJ, Barrangou R, Brouns SJJ, Charpentier E, Haft DH, Horvath P, Moineau S, Mojica FJM, Terns RM, Terns MP, White MF, Yakunin AF, Garrett RA, van der Oost J, Backofen R, Koonin EV (2015) An updated evolutionary classification of CRISPR-Cas systems. Nat Rev Microbiol 13:722–736. doi: 10.1038/nrmicro3569 PubMedPubMedCentralCrossRefGoogle Scholar
  95. Mauban JRH, O’Donnell M, Warrier S, Manni S, Bond M (2009) AKAP-scaffolding proteins and regulation of cardiac physiology. Physiology (Bethesda) 24:78–87. doi: 10.1152/physiol.00041.2008 Google Scholar
  96. McConnell BK, Popovic Z, Mal N, Lee K, Bautista J, Forudi F, Schwartzman R, Jin JP, Penn M, Bond M (2009) Disruption of protein kinase A interaction with A-kinase-anchoring proteins in the heart in vivo: effects on cardiac contractility, protein kinase A phosphorylation, and troponin I proteolysis. J Biol Chem 284:1583–1592. doi: 10.1074/jbc.M806321200 PubMedPubMedCentralCrossRefGoogle Scholar
  97. Newlon MG, Roy M, Morikis D, Hausken ZE, Coghlan V, Scott JD, Jennings PA (1999) The molecular basis for protein kinase A anchoring revealed by solution NMR. Nat Struct Mol Biol 6:222–227. doi: 10.1038/6663 CrossRefGoogle Scholar
  98. Newlon MG, Roy M, Morikis D, Carr DW, Westphal R, Scott JD, Jennings PA (2001) A novel mechanism of PKA anchoring revealed by solution structures of anchoring complexes. EMBO J 20:1651. doi: 10.1093/emboj/20.7.1651 PubMedPubMedCentralCrossRefGoogle Scholar
  99. Nichols CB, Rossow CF, Navedo MF, Westenbroek RE, Catterall WA, Santana LF, McKnight GS (2010) Sympathetic stimulation of adult cardiomyocytes requires association of AKAP5 with a subpopulation of L-type calcium channels. Circ Res 107:747–756. doi: 10.1161/CIRCRESAHA.109.216127 PubMedCrossRefGoogle Scholar
  100. Nystoriak MA, Nieves-Cintrón M, Nygren PJ, Hinke SA, Nichols CB, Chen C-Y, Puglisi JL, Izu LT, Bers DM, Dell’acqua ML, Scott JD, Santana LF, Navedo MF (2014) AKAP150 contributes to enhanced vascular tone by facilitating large-conductance Ca2+-activated K+ channel remodeling in hyperglycemia and diabetes mellitus. Circ Res 114:607–615. doi: 10.1161/CIRCRESAHA.114.302168
  101. Oliveria SF, Dell’Acqua ML, Sather WA (2007) AKAP79/150 anchoring of calcineurin controls neuronal L-type Ca2+ channel activity and nuclear signaling. Neuron 55:261–275. doi: 10.1016/j.neuron.2007.06.032 PubMedPubMedCentralCrossRefGoogle Scholar
  102. Otvos L, Wade JD (2014) Current challenges in peptide-based drug discovery. Front Chem 2:62. doi: 10.3389/fchem.2014.00062 PubMedPubMedCentralGoogle Scholar
  103. Pannekoek W-J, Kooistra MRH, Zwartkruis FJT, Bos JL (2009) Cell–cell junction formation: the role of Rap1 and Rap1 guanine nucleotide exchange factors. Biochim Biophys Acta 1788:790–796. doi: 10.1016/j.bbamem.2008.12.010 PubMedCrossRefGoogle Scholar
  104. Pannekoek WJ, Linnemann JR, Brouwer PM, Bos JL, Rehmann H (2013) Rap1 and Rap2 antagonistically control endothelial barrier resistance. PLoS One 8:e57903. doi: 10.1371/journal.pone.0057903 PubMedPubMedCentralCrossRefGoogle Scholar
  105. Pare GC, Bauman AL, McHenry M, Michel JJC, Dodge-Kafka KL, Kapiloff MS (2005) The mAKAP complex participates in the induction of cardiac myocyte hypertrophy by adrenergic receptor signaling. J Cell Sci 118:5637–5646. doi: 10.1242/jcs.02675 PubMedCrossRefGoogle Scholar
  106. Pastor-Soler N, Beaulieu V, Litvin TN, Silva ND, Chen Y, Brown D, Buck J, Levin LR, Breton S (2003) Bicarbonate-regulated adenylyl cyclase (sAC) is a sensor that regulates pH-dependent V-ATPase recycling. J Biol Chem 278:49523–49529. doi: 10.1074/jbc.M309543200 PubMedPubMedCentralCrossRefGoogle Scholar
  107. Patel HH, Hamuro LL, Chun BJ, Kawaraguchi Y, Quick A, Rebolledo B, Pennypacker J, Thurston J, Rodriguez-Pinto N, Self C, Olson G, Insel PA, Giles WR, Taylor SS, Roth DM (2010) Disruption of protein kinase A localization using a trans-activator of transcription (TAT)-conjugated A-kinase-anchoring peptide reduces cardiac function. J Biol Chem 285:27632. doi: 10.1074/jbc.M110.146589 PubMedPubMedCentralCrossRefGoogle Scholar
  108. Pidoux G, Witczak O, Jarnæss E, Myrvold L, Urlaub H, Stokka AJ, Küntziger T, Taskén K (2011) Optic atrophy 1 is an A-kinase anchoring protein on lipid droplets that mediates adrenergic control of lipolysis. EMBO J 30:4371. doi: 10.1038/emboj.2011.365 PubMedPubMedCentralCrossRefGoogle Scholar
  109. Poppinga WJ, Muñoz-Llancao P, González-Billault C, Schmidt M (2014) A-kinase anchoring proteins: cAMP compartmentalization in neurodegenerative and obstructive pulmonary diseases. Br J Pharmacol 171:5603–5623. doi: 10.1111/bph.12882 PubMedPubMedCentralCrossRefGoogle Scholar
  110. Poulsen JB, Andersen KR, Kjær KH, Vestergaard AL, Justesen J, Martensen PM (2012) Characterization of human phosphodiesterase 12 and identification of a novel 2′-5′ oligoadenylate nuclease—the ectonucleotide pyrophosphatase/phosphodiesterase 1. Biochimie 94:1098–1107. doi: 10.1016/j.biochi.2012.01.012 PubMedCrossRefGoogle Scholar
  111. Rehmann H (2006) Characterization of the activation of the Rap-specific exchange factor Epac by cyclic nucleotides. Methods Enzymol 407:159–173.Google Scholar
  112. de Rooij J, Zwartkruis FJT, Verheijen MHG, Cool RH, Nijman SMB, Wittinghofer A, Bos JL (1998) Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP. Nature 396:474–477. doi: 10.1038/24884 PubMedCrossRefGoogle Scholar
  113. Saliba J, Saint-Martin C, Di Stefano A, Lenglet G, Marty C, Keren B, Pasquier F, Valle VD, Secardin L, Leroy G, Mahfoudhi E, Grosjean S, Droin N, Diop M, Dessen P, Charrier S, Palazzo A, Merlevede J, Meniane JC, Delaunay-Darivon C, Fuseau P, Isnard F, Casadevall N, Solary E, Debili N, Bernard OA, Raslova H, Najman A, Vainchenker W, Bellanné-Chantelot C, Plo I (2015) Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies. Nat Genet 47:1131–1140. doi: 10.1038/ng.3380 PubMedCrossRefGoogle Scholar
  114. Sarma GN, Kinderman FS, Kim C, von Daake S, Chen L, Wang B-C, Taylor SS (2010) Structure of D-AKAP2:PKA RI complex: insights into AKAP specificity and selectivity. Struct Lond Engl 1993(18):155–166. doi: 10.1016/j.str.2009.12.012 Google Scholar
  115. Sassi Y, Ahles A, Truong DJ, Baqi Y, Lee SY, Husse B, Hulot JS, Foinquinos A, Thum T, Müller CE, Dendorfer A, Laggerbauer B, Engelhardt S (2014) Cardiac myocyte-secreted cAMP exerts paracrine action via adenosine receptor activation. J Clin Invest 124:5385–5397. doi: 10.1172/JCI74349 PubMedPubMedCentralCrossRefGoogle Scholar
  116. Schächterle C, Christian F, Fernandes J, Klussmann E (2015) Screening for small molecule disruptors of AKAP–PKA interactions. In: Zaccolo M (ed) cAMP signaling, methods in molecular biology. Springer, New York, pp 151–166Google Scholar
  117. Schäfer G, Milić J, Eldahshan A, Götz F, Zühlke K, Schillinger C, Kreuchwig A, Elkins JM, Abdul Azeez KR, Oder A, Moutty MC, Masada N, Beerbaum M, Schlegel B, Niquet S, Schmieder P, Krause G, von Kries JP, Cooper DMF, Knapp S, Rademann J, Rosenthal W, Klussmann E (2013) Highly functionalized terpyridines as competitive inhibitors of AKAP–PKA interactions. Angew Chem Int Ed 52:12187–12191. doi: 10.1002/anie.201304686 CrossRefGoogle Scholar
  118. Schafmeister CE, Po J, Verdine GL (2000) An all-hydrocarbon cross-linking system for enhancing the Helicity and metabolic stability of peptides. J Am Chem Soc 122:5891–5892. doi: 10.1021/ja000563a CrossRefGoogle Scholar
  119. Scott JD, Glaccum MB, Zoller MJ, Uhler MD, Helfman DM, McKnight GS, Krebs EG (1987) The molecular cloning of a type II regulatory subunit of the cAMP-dependent protein kinase from rat skeletal muscle and mouse brain. Proc Natl Acad Sci U S A 84:5192–5196PubMedPubMedCentralCrossRefGoogle Scholar
  120. Scott DE, Bayly AR, Abell C, Skidmore J (2016) Small molecules, big targets: drug discovery faces the protein-protein interaction challenge. Nat Rev Drug Discov. doi: 10.1038/nrd.2016.29 PubMedGoogle Scholar
  121. Shabb JB (2001) Physiological substrates of cAMP-dependent protein kinase. Chem Rev 101:2381–2412. doi: 10.1021/cr000236l PubMedCrossRefGoogle Scholar
  122. Singh M, Singh P, Vaira D, Torheim EA, Rahmouni S, Taskén K, Moutschen M (2014) The RIAD peptidomimetic inhibits HIV-1 replication in humanized NSG mice. Eur J Clin Investig 44:146–152. doi: 10.1111/eci.12200 CrossRefGoogle Scholar
  123. Siu YT, Jin DY (2007) CREB—a real culprit in oncogenesis. FEBS J 274:3224–3232. doi: 10.1111/j.1742-4658.2007.05884.x PubMedCrossRefGoogle Scholar
  124. Skalhegg BS, Tasken K (2000) Specificity in the cAMP/PKA signaling pathway. Differential expression, regulation, and subcellular localization of subunits of PKA. Front Biosci J Virtual Libr 5:D678–D693Google Scholar
  125. Skroblin P, Grossmann S, Schäfer G, Rosenthal W, Klussmann E (2010) Chapter five—mechanisms of protein kinase A anchoring. In: Jeon K (ed) International review of cell and molecular biology. Academic Press, New York, pp 235–330Google Scholar
  126. Smith MC, Gestwicki JE (2012) Features of protein–protein interactions that translate into potent inhibitors: topology, surface area and affinity. Expert Rev Mol Med 14:e16. doi: 10.1017/erm.2012.10 PubMedPubMedCentralCrossRefGoogle Scholar
  127. Soni S, Scholten A, Vos MA, Veen TAB (2014) Anchored protein kinase A signalling in cardiac cellular electrophysiology. J Cell Mol Med 18:2135–2146. doi: 10.1111/jcmm.12365 PubMedPubMedCentralCrossRefGoogle Scholar
  128. Sonkusare SK, Dalsgaard T, Bonev AD, Hill-Eubanks DC, Kotlikoff MI, Scott JD, Santana LF, Nelson MT (2014) AKAP150-dependent cooperative TRPV4 channel gating is central to endothelium-dependent vasodilation and is disrupted in hypertension. Sci Signal 7(333):ra66. doi: 10.1126/scisignal.2005052 PubMedPubMedCentralCrossRefGoogle Scholar
  129. Steegborn C (2014) Structure, mechanism, and regulation of soluble adenylyl cyclases—similarities and differences to transmembrane adenylyl cyclases. Biochim Biophys Acta 1842(12 Pt B):2535–2547. doi: 10.1016/j.bbadis.2014.08.012 PubMedCrossRefGoogle Scholar
  130. Stefan E, Wiesner B, Baillie GS, Mollajew R, Henn V, Lorenz D, Furkert J, Santamaria K, Nedvetsky P, Hundsrucker C, Beyermann M, Krause E, Pohl P, Gall I, MacIntyre AN, Bachmann S, Houslay MD, Rosenthal W, Klussmann E (2007) Compartmentalization of cAMP-dependent signaling by phosphodiesterase-4D is involved in the regulation of vasopressin-mediated water reabsorption in renal principal cells. J Am Soc Nephrol 18:199–212. doi: 10.1681/ASN.2006020132 PubMedCrossRefGoogle Scholar
  131. Subrizi A, Tuominen E, Bunker A, Róg T, Antopolsky M, Urtti A (2012) Tat(48–60) peptide amino acid sequence is not unique in its cell penetrating properties and cell-surface glycosaminoglycans inhibit its cellular uptake. J Control Release Off J Control Release Soc 158:277–285. doi: 10.1016/j.jconrel.2011.11.007 CrossRefGoogle Scholar
  132. Sutherland EW, Rall TW (1958) Fractionation and characterization of a cyclic adenine ribonucleotide formed by tissue particles. J Biol Chem 232:1077–1092PubMedGoogle Scholar
  133. Szaszak M, Christian F, Rosenthal W, Klussmann E (2008) Compartmentalized cAMP signalling in regulated exocytic processes in non-neuronal cells. Cell Signal 20:590–601PubMedCrossRefGoogle Scholar
  134. Taglieri DM, Johnson KR, Burmeister BT, Monasky MM, Spindler MJ, DeSantiago J, Banach K, Conklin BR, Carnegie GK (2014) The C-terminus of the long AKAP13 isoform (AKAP-Lbc) is critical for development of compensatory cardiac hypertrophy. J Mol Cell Cardiol 66:27–40. doi: 10.1016/j.yjmcc.2013.10.010 PubMedCrossRefGoogle Scholar
  135. Tavalin SJ (2008) AKAP79 selectively enhances protein kinase C regulation of GluR1 at a Ca2+-calmodulin-dependent protein kinase II/protein kinase C site. J Biol Chem 283:11445–11452. doi: 10.1074/jbc.M709253200 PubMedPubMedCentralCrossRefGoogle Scholar
  136. Taylor SS, Ilouz R, Zhang P, Kornev AP (2012) Assembly of allosteric macromolecular switches: lessons from PKA. Nat Rev Mol Cell Biol 13:646. doi: 10.1038/nrm3432 PubMedPubMedCentralCrossRefGoogle Scholar
  137. Taylor SS, Zhang P, Steichen JM, Keshwani MM, Kornev AP (2013) PKA: lessons learned after twenty years. Biochim Biophys Acta 1834:1271. doi: 10.1016/j.bbapap.2013.03.007 PubMedPubMedCentralCrossRefGoogle Scholar
  138. Terato K, Do CT, Cutler D, Waritani T, Shionoya H (2014) Preventing intense false positive and negative reactions attributed to the principle of ELISA to re-investigate antibody studies in autoimmune diseases. J Immunol Methods 407:15–25. doi: 10.1016/j.jim.2014.03.013 PubMedCrossRefGoogle Scholar
  139. Torheim EA, Jarnæss E, Lygren B, Taskén K (2009) Design of proteolytically stable RI-anchoring disruptor peptidomimetics for in vivo studies of anchored type I protein kinase A-mediated signalling. Biochem J 424:69–78. doi: 10.1042/BJ20090933 PubMedCrossRefGoogle Scholar
  140. Tsien RY, Bacskai BJ, Adams SR (1993) FRET for studying intracellular signalling. Trends Cell Biol 3:242–245. doi: 10.1016/0962-8924(93)90124-J PubMedCrossRefGoogle Scholar
  141. Vivès E, Brodin P, Lebleu B (1997) A truncated HIV-1 tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus. J Biol Chem 272:16010–16017. doi: 10.1074/jbc.272.25.16010 PubMedCrossRefGoogle Scholar
  142. Vukićević T, Schulz M, Faust D, Klussmann E (2016) The trafficking of the water channel aquaporin-2 in renal principal cells-a potential target for pharmacological intervention in cardiovascular diseases. Front Pharmacol 7:23. doi: 10.3389/fphar.2016.00023 PubMedPubMedCentralCrossRefGoogle Scholar
  143. Walensky LD, Kung AL, Escher I, Malia TJ, Barbuto S, Wright RD, Wagner G, Verdine GL, Korsmeyer SJ (2004) Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science 305:1466. doi: 10.1126/science.1099191 PubMedPubMedCentralCrossRefGoogle Scholar
  144. Walsh DA, Perkins JP, Krebs EG (1968) An adenosine 3′,5′-monophosphate-dependant protein kinase from rabbit skeletal muscle. J Biol Chem 243:3763–3765PubMedGoogle Scholar
  145. Wang Y, Ho TG, Bertinetti D, Neddermann M, Franz E, Mo GCH, Schendowich LP, Sukhu A, Spelts RC, Zhang J, Herberg FW, Kennedy EJ (2014) Isoform-selective disruption of AKAP-localized PKA using hydrocarbon stapled peptides. ACS Chem Biol 9:635–642. doi: 10.1021/cb400900r PubMedPubMedCentralCrossRefGoogle Scholar
  146. Wang Y, Ho TG, Franz E, Hermann JS, Smith FD, Hehnly H, Esseltine JL, Hanold LE, Murph MM, Bertinetti D, Scott JD, Herberg FW, Kennedy EJ (2015) PKA-type I selective constrained peptide disruptors of AKAP complexes. ACS Chem Biol 10:1502–1510. doi: 10.1021/acschembio.5b00009 PubMedPubMedCentralCrossRefGoogle Scholar
  147. Wechsler J, Choi YH, Krall J, Ahmad F, Manganiello VC, Movsesian MA (2002) Isoforms of cyclic nucleotide phosphodiesterase PDE3A in cardiac myocytes. J Biol Chem 277:38072–38078. doi: 10.1074/jbc.M203647200 PubMedCrossRefGoogle Scholar
  148. Wehrens XHT, Lehnart SE, Reiken S, Vest JA, Wronska A, Marks AR (2006) Ryanodine receptor/calcium release channel PKA phosphorylation: a critical mediator of heart failure progression. Proc Natl Acad Sci U S A 103:511–518. doi: 10.1073/pnas.0510113103 PubMedPubMedCentralCrossRefGoogle Scholar
  149. Weiss S, Oz S, Benmocha A, Dascal N (2013) Regulation of cardiac L-type Ca2+ channel CaV1.2 via the β-adrenergic-cAMP-protein kinase A pathway: old dogmas, advances, and new uncertainties. Circ Res 113:617–631. doi: 10.1161/CIRCRESAHA.113.301781 PubMedCrossRefGoogle Scholar
  150. Wetzel CH, Spehr M, Hatt H (2001) Phosphorylation of voltage-gated ion channels in rat olfactory receptor neurons. Eur J Neurosci 14:1056–1064PubMedCrossRefGoogle Scholar
  151. White BD, Chien AJ, Dawson DW (2012) Dysregulation of Wnt/β-catenin signaling in gastrointestinal cancers. Gastroenterology 142:219–232. doi: 10.1053/j.gastro.2011.12.001 PubMedCrossRefGoogle Scholar
  152. Willoughby D, Cooper DMF (2008) Live-cell imaging of cAMP dynamics. Nat Methods 5:29–36. doi: 10.1038/nmeth1135 PubMedCrossRefGoogle Scholar
  153. Wu ZL, Thomas SA, Villacres EC, Xia Z, Simmons ML, Chavkin C, Palmiter RD, Storm DR (1995) Altered behavior and long-term potentiation in type I adenylyl cyclase mutant mice. Proc Natl Acad Sci 92:220–224PubMedPubMedCentralCrossRefGoogle Scholar
  154. Wu J, Brown SHJ, von Daake S, Taylor SS (2007) PKA type IIα holoenzyme reveals a combinatorial strategy for isoform diversity. Science 318:274. doi: 10.1126/science.1146447 PubMedPubMedCentralCrossRefGoogle Scholar
  155. Zaccolo M, Pozzan T (2002) Discrete microdomains with high concentration of cAMP in stimulated rat neonatal cardiac myocytes. Science 295:1711–1715. doi: 10.1126/science.1069982 PubMedCrossRefGoogle Scholar
  156. Zaccolo M, De Giorgi F, Cho CY, Feng L, Knapp T, Negulescu PA, Taylor SS, Tsien RY, Pozzan T (2000) A genetically encoded, fluorescent indicator for cyclic AMP in living cells. Nat Cell Biol 2:25–29. doi: 10.1038/71345 PubMedCrossRefGoogle Scholar
  157. Zhang L, Malik S, Kelley GG, Kapiloff MS, Smrcka AV (2011) Phospholipase C epsilon scaffolds to muscle-specific A kinase anchoring protein (mAKAPbeta) and integrates multiple hypertrophic stimuli in cardiac myocytes. J Biol Chem 286:23012–23021. doi: 10.1074/jbc.M111.231993 PubMedPubMedCentralCrossRefGoogle Scholar
  158. Zhang M, Patriarchi T, Stein IS, Qian H, Matt L, Nguyen M, Xiang YK, Hell JW (2013) Adenylyl cyclase anchoring by a kinase anchor protein AKAP5 (AKAP79/150) is important for postsynaptic β-adrenergic signaling. J Biol Chem 288:17918–17931. doi: 10.1074/jbc.M112.449462 PubMedPubMedCentralCrossRefGoogle Scholar

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© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Max Delbrueck Center for Molecular Medicine Berlin (MDC) in the Helmholtz AssociationBerlinGermany
  2. 2.DZHK (German Centre for Cardiovascular Research)BerlinGermany

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