Skip to main content
SpringerLink
Log in
Book cover

Microdomains in the Cardiovascular System pp 161–173Cite as

Cardiac cAMP Microdomains and Their Modulation Using Disruptor Peptides

  • Chapter
  • First Online:

  • 713 Accesses

Part of the book series: Cardiac and Vascular Biology ((Abbreviated title: Card. vasc. biol.,volume 3))

Abstract

PDEs are an important superfamily of enzymes that regulate dynamic gradients of cyclic nucleotides. The plethora of isoforms that can be generated from the 11 families are selectively expressed and targeted in cellular microdomains, with each isoform’s function underpinned by its location, affinity/specificity of its cyclic nucleotide substrate, and ability to be modified by posttranslational modifications. The best way to define the function of a particular “pool” of PDE within a cell is to displace the active protein from its site of action. As many PDE isoforms have multiple functions within the same or closely related cell types, pharmacological inhibition, silencing with siRNA, or dominant negative approaches can only reveal functional changes that are a product of the attenuation of the activity of an isoform in all its possible locations. To allow a more detailed appreciation of the role of cyclic nucleotide signaling in cellular microdomains, peptides directed at sequences that serve to anchor individual enzymes to discrete cellular locations have been devised to displace endogenous, active PDE “pools.” As this approach is not directed at the active site of the PDE, global PDE activity within the cell remains unaltered, while confined microdomains experience increases in cyclic nucleotide concentration that may alter PKA-directed modifications of local substrates or promote inappropriate EPAC activation. This chapter reviews recent developments in the disruption of cAMP signalosomes using specific disruptor peptides.

This is a preview of subscription content, log in via an institution.

References

  • Ahrens VM, Bellmann-Sickert K, Beck-Sickinger AG (2012) Peptides and peptide conjugates: therapeutics on the upward path. Future Med Chem 4(12):1567–1586

    Article  CAS  PubMed  Google Scholar 

  • 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(8):4445–4450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • An SS, Askovich PS, Zarembinski TI, Ahn K, Peltier JM, Von Rechenberg M, Sahasrabudhe S, Fredberg JJ (2011) A novel small molecule target in human airway smooth muscle for potential treatment of obstructive lung diseases: a staged high-throughput biophysical screening. Respir Res 12:8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baillie GS, Houslay MD (2005) Arrestin times for compartmentalised cAMP signalling and phosphodiesterase-4 enzymes. Curr Opin Cell Biol 17(2):129–134

    Article  CAS  PubMed  Google Scholar 

  • Baillie GS, Huston E, Scotland G, Hodgkin M, Gall I, Peden AH, MacKenzie C, Houslay ES, Currie R, Pettitt TR, Walmsley AR, Wakelam MJ, 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(31):28298–28309

    Article  CAS  PubMed  Google Scholar 

  • Baillie GS, Sood A, McPhee I, Gall I, Perry SJ, Lefkowitz RJ, Houslay MD (2003) beta-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates beta-adrenoceptor switching from Gs to Gi. Proc Natl Acad Sci U S A 100(3):940–945

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baillie GS, Adams DR, Bhari N, Houslay TM, Vadrevu S, Meng D, Li X, Dunlop A, Milligan G, Bolger GB, Klussmann E, Houslay MD (2007) Mapping binding sites for the PDE4D5 cAMP-specific phosphodiesterase to the N- and C-domains of beta-arrestin using spot-immobilized peptide arrays. Biochem J 404(1):71–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beall A, Bagwell D, Woodrum D, Stoming TA, Kato K, Suzuki A, Rasmussen H, Brophy CM (1999) The small heat shock-related protein, HSP20, is phosphorylated on serine 16 during cyclic nucleotide-dependent relaxation. J Biol Chem 274(16):11344–11351

    Article  CAS  PubMed  Google Scholar 

  • Berthouze-Duquesnes M, Lucas A, Sauliere A, Sin YY, Laurent AC, Gales C, Baillie GS, Lezoualc’h F (2012) Specific interactions between Epac1, beta-arrestin2 and PDE4D5 regulate beta-adrenergic receptor subtype differential effects on cardiac hypertrophic signaling. Cell Signal 25(4):970–980

    Article  PubMed  CAS  Google Scholar 

  • Bialek K, Swistowski A, Frank R (2003) Epitope-targeted proteome analysis: towards a large-scale automated protein-protein-interaction mapping utilizing synthetic peptide arrays. Anal Bioanal Chem 376(7):1006–1013

    Article  CAS  PubMed  Google Scholar 

  • Bolger GB, McCahill A, Huston E, Cheung YF, McSorley T, Baillie GS, Houslay MD (2003a) The unique amino-terminal region of the PDE4D5 cAMP phosphodiesterase isoform confers preferential interaction with beta-arrestins. J Biol Chem 278(49):49230–49238

    Article  CAS  PubMed  Google Scholar 

  • Bolger GB, Peden AH, Steele MR, MacKenzie C, McEwan DG, Wallage DA, Huston E, Baillie GS, Houslay MD (2003b) Attenuation of the activity of the cAMP-specific phosphodiesterase PDE4A5 by interaction with the immunophilin XAP2. J Biol Chem 278(35):33351–33363

    Article  CAS  PubMed  Google Scholar 

  • Bolger GB, Baillie Gs, Li X, Lynch MJ, Herzyk P, Mohamed A, Mitchell LH, McCahill A, Hundsrucker C, Klussman E, Adams DR, Christian F, Szaszak M, Friedl S, Drewianka S, Lorenz D, Goncalves A, Furkert J, Vargas C, Schmieder P, Gotz F, Zuhlke K, Moutty M, Gottert H, Joshi M, Reif B, Haase H, Morano I, Grossmann S, Klukovits A, Verli J, Gaspar R, Noack C, Bergmann M, Kass R, Hampel K, Kashin D, Genieser HG, Herberg FW, Willoughby D, Cooper DM, 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(11):9079–9096

    Article  CAS  Google Scholar 

  • Bos JL (2006) Epac proteins: multi-purpose cAMP targets. Trends Biochem Sci 31(12):680–686

    Article  CAS  PubMed  Google Scholar 

  • Brown KM, Lee LC, Findlay JE, Day JP, Baillie GS (2012) Cyclic AMP-specific phosphodiesterase, PDE8A1, is activated by protein kinase A-mediated phosphorylation. FEBS Lett 586(11):1631–1637

    Article  CAS  PubMed  Google Scholar 

  • Carlson CR, Lygren B, Berge T, Hoshi N, Wong W, Tasken K, Scott JD (2006) Delineation of type I protein kinase A-selective signaling events using an RI anchoring disruptor. J Biol Chem 281(30):21535–21545

    Article  CAS  PubMed  Google Scholar 

  • Christian F. et al. (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(11):9079–9096

    Article  CAS  Google Scholar 

  • Conti M, Beavo J (2007) Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem 76:481–511

    Article  CAS  PubMed  Google Scholar 

  • Dreiza CM, Brophy CM, Komalavilas P, Furnish EJ, Joshi L, Pallero MA, Murphy-Ullrich JE, von Rechenberg M, Ho YS, Richardson B, Xu N, Zhen Y, Peltier JM, Panitch A (2005) Transducible heat shock protein 20 (HSP20) phosphopeptide alters cytoskeletal dynamics. FASEB J 19(2):261–263

    Article  CAS  PubMed  Google Scholar 

  • Edwards HV, Scott JD, Baillie GS (2012a) The A-kinase-anchoring protein AKAP-Lbc facilitates cardioprotective PKA phosphorylation of Hsp20 on Ser(16). Biochem J 446(3):437–443

    Article  CAS  PubMed  Google Scholar 

  • Edwards HV, Scott JD, Baillie GS (2012b) PKA phosphorylation of the small heat-shock protein Hsp20 enhances its cardioprotective effects. Biochem Soc Trans 40(1):210–214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fan GC, Chu G, Kranias EG (2005) Hsp20 and its cardioprotection. Trends Cardiovasc Med 15(4):138–141

    Article  CAS  PubMed  Google Scholar 

  • 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(3):291–297

    Article  CAS  PubMed  Google Scholar 

  • Gorelik J, Wright PT, Lyon AR, Harding SE (2013) Spatial control of the betaAR system in heart failure: the transverse tubule and beyond. Cardiovasc Res 98(2):216–224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Horvat SJ, Deshpande DA, Yan H, Panettieri RA, Codina J, DuBose TD, Xin W, Rich TC, Penn RB (2012) A-kinase anchoring proteins regulate compartmentalized cAMP signaling in airway smooth muscle. FASEB J 26(9):3670–3679

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Houslay MD, Adams DR (2003) PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem J 370(Pt 1):1–18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Houslay MD, Baillie GS, Maurice DH (2007) cAMP-Specific phosphodiesterase-4 enzymes in the cardiovascular system: a molecular toolbox for generating compartmentalized cAMP signaling. Circ Res 100(7):950–966

    Article  CAS  PubMed  Google Scholar 

  • Hundsrucker C, Krause G, Beyermann M, Prinz A, Zimmermann B, Diekmann O, Lorenz D, Stephan E, Nedvetsky P, Dathe M, Christian F, McSorley T, Krause E, McConnachie G, Herberg FW, Scott JD, Rosenthal W, Klussmann E (2006) High-affinity AKAP7delta-protein kinase A interaction yields novel protein kinase A-anchoring disruptor peptides. Biochem J 396(2):297–306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaupp UB, Seifert R (2002) Cyclic nucleotide-gated ion channels. Physiol Rev 82(3):769–824

    Article  CAS  PubMed  Google Scholar 

  • Komalavilas P, Penn RB, Flynn CR, Thresher J, Lopes LB, Furnish EJ, Guo M, Pallero MA, Murphy-Ulrich JE, Brophy CM (2008) The small heat shock-related protein, HSP20, is a cAMP-dependent protein kinase substrate that is involved in airway smooth muscle relaxation. Am J Physiol Lung Cell Mol Physiol 294(1):L69–L78

    Article  CAS  PubMed  Google Scholar 

  • Lee JH, Jung NH, Lee BH, Kim SH, Jun JH (2013a) Suppression of Heme Oxygenase-1 by prostaglandin E2-protein kinase A-A-kinase anchoring protein signaling is central for augmented cyclooxygenase-2 expression in lipopolysaccharide-stimulated RAW 264.7 macrophages. Allergy Asthma Immunol Res 5(5):329–336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee LC, Maurice DH, Baillie GS (2013b) Targeting protein-protein interactions within the cyclic AMP signaling system as a therapeutic strategy for cardiovascular disease. Future Med Chem 5(4):451–464

    Article  CAS  PubMed  Google Scholar 

  • Li SS, Wu C (2009) Using peptide array to identify binding motifs and interaction networks for modular domains. Methods Mol Biol 570:67–76

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Sroubek J, Krishnan Y, McDonald TV (2008) A-kinase anchoring protein targeting of protein kinase A and regulation of HERG channels. J Membr Biol 223(2):107–116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li X, Baillie GS, Houslay MD (2009) Mdm2 directs the ubiquitination of beta-arrestin-sequestered cAMP phosphodiesterase-4D5. J Biol Chem 284(24):16170–16182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lynch MJ, Baillie GS, Mohamed A, Maisonneuve C, Klussmann E, van Heeke G, Houslay MD (2005) RNA silencing identifies PDE4D5 as the functionally relevant cAMP phosphodiesterase interacting with beta arrestin to control the protein kinase A/AKAP79-mediated switching of the beta2-adrenergic receptor to activation of ERK in HEK293B2 cells. J Biol Chem 280(39):33178–33189

    Article  CAS  PubMed  Google Scholar 

  • Martin TP, Currie S, Baillie GS (2014a) The cardioprotective role of small heat-shock protein 20. Biochem Soc Trans 42(2):270–273

    Article  CAS  PubMed  Google Scholar 

  • Martin TP, Hortingon-Vinagre MP, Findlay JE, Elliott C, Currie S, Baillie GS (2014b) Targeted disruption of the heat shock protein 20-phosphodiesterase 4D (PDE4D) interaction protects against pathological cardiac remodelling in a mouse model of hypertrophy. FEBS Open Bio 4:923–927

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mauban JR, O’Donnell M, Warrier S, Manni S, Bond M (2009) AKAP-scaffolding proteins and regulation of cardiac physiology. Physiology (Bethesda) 24:78–87

    CAS  Google Scholar 

  • Maurice DH, Ke H, Ahmad F, Wang Y, Chung J, Manganiello VC (2014) Advances in targeting cyclic nucleotide phosphodiesterases. Nat Rev Drug Discov 13(4):290–314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McConnachie G, Langeberg LK, Scott JD (2006) AKAP signaling complexes: getting to the heart of the matter. Trends Mol Med 12(7):317–323

    Article  CAS  PubMed  Google Scholar 

  • McCormick K, Baillie GS (2014) Compartmentalisation of second messenger signalling pathways. Curr Opin Genet Dev 27:20–25

    Article  CAS  PubMed  Google Scholar 

  • Murdoch H, Vadrevu S, Prinz A, Dunlop AJ, Klussmann E, Bolger GB, Norman JC, Houslay MD (2011) Interaction between LIS1 and PDE4, and its role in cytoplasmic dynein function. J Cell Sci 124(Pt 13):2253–2266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nikolaev VO, Moshkov A, Lyon AR, Miragoli M, Novak P, Paur H, Lohse MJ, Korchev YE, Harding SE, Gorelik J (2010) Beta2-adrenergic receptor redistribution in heart failure changes cAMP compartmentation. Science 327(5973):1653–1657

    Article  CAS  PubMed  Google Scholar 

  • Nino G, Hu A, Grunstein JS, Grunstein MM (2009) Mechanism regulating proasthmatic effects of prolonged homologous beta2-adrenergic receptor desensitization in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 297(4):L746–L757

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patel HH, Hamuro LL, Chun BJ, Kawaraguchi Y, Quick A, Rebolledo B, Pennypacker J, Thurston J, Rodriquez-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(36):27632–27640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perry SJ, Baillie GS, Kohout TA, McPhee I, Magiera MM, Ang KL, Miller WE, McLean AJ, Conti M, Houslay MD, Lefkowitz RJ (2002) Targeting of cyclic AMP degradation to beta 2-adrenergic receptors by beta-arrestins. Science 298(5594):834–836

    Article  CAS  PubMed  Google Scholar 

  • Rampersad SN, Ovens JD, Huston E, Umana MB, Wilson LS, Netherton SJ, Lynch MJ, Baillie GS, Houslay MD, Maurice DH (2010) Cyclic AMP phosphodiesterase 4D (PDE4D) Tethers EPAC1 in a vascular endothelial cadherin (VE-Cad)-based signaling complex and controls cAMP-mediated vascular permeability. J Biol Chem 285(44):33614–33622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rangarajan S, Enserink JM, Kuiperij HB, de Rooij J, Price LS, Schwede F, Bos JL (2003) Cyclic AMP induces integrin-mediated cell adhesion through Epac and Rap1 upon stimulation of the beta 2-adrenergic receptor. J Cell Biol 160(4):487–493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Raslan Z, Magwenzi S, Aburima A, Tasken K, Naseem KM (2015) Targeting of type I protein kinase A to lipid rafts is required for platelet inhibition by the 3',5'-cyclic adenosine monophosphate-signaling pathway. J Thromb Haemost 13(9):1721–1734

    Article  CAS  PubMed  Google Scholar 

  • Sachs BD, Baillie GS, McCall JR, Passino MA, Schachtrup C, Wallace DA, Dunlop AJ, MacKenzie KF, Klussmann E, Lynch MJ, Sikorski SL, Nuriel T, Tsigelny I, Zhang J, Houslay MD, Chao MV, Akassoglou K (2007) p75 neurotrophin receptor regulates tissue fibrosis through inhibition of plasminogen activation via a PDE4/cAMP/PKA pathway. J Cell Biol 177(6):1119–1132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schindler RF, Brand T (2016) The Popeye domain containing protein family—a novel class of cAMP effectors with important functions in multiple tissues. Prog Biophys Mol Biol 120(1–3):28–36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scotland G, Houslay MD (1995) Chimeric constructs show that the unique N-terminal domain of the cyclic AMP phosphodiesterase RD1 (RNPDE4A1A; rPDE-IVA1) can confer membrane association upon the normally cytosolic protein chloramphenicol acetyltransferase. Biochem J 308(Pt 2):673–681

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sin YY, Edwards HV, Li X, Day JP, Christian F, Dunlop AJ, Adams DR, Zaccolo M, Houslay MD, Baillie GS (2011) Disruption of the cyclic AMP phosphodiesterase-4 (PDE4)-HSP20 complex attenuates the beta-agonist induced hypertrophic response in cardiac myocytes. J Mol Cell Cardiol 50(5):872–883

    Article  CAS  PubMed  Google Scholar 

  • Smith KJ, Baillie GS, Hyde EI, Li X, Houslay TM, McCahill A, Dunlop AJ, Bolger GB, Klussman E, Adams DR, Houslay MD (2007) 1H NMR structural and functional characterisation of a cAMP-specific phosphodiesterase-4D5 (PDE4D5) N-terminal region peptide that disrupts PDE4D5 interaction with the signalling scaffold proteins, beta-arrestin and RACK1. Cell Signal 19(12):2612–2624

    Article  CAS  PubMed  Google Scholar 

  • Taylor RP, Benjamin IJ (2005) Small heat shock proteins: a new classification scheme in mammals. J Mol Cell Cardiol 38(3):433–444

    Article  CAS  PubMed  Google Scholar 

  • Taylor SS, Zhang P, Steichen JM, Keshwani MM, Kornev AP (2013) PKA: lessons learned after twenty years. Biochim Biophys Acta 1834(7):1271–1278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang L, Burmeister BT, Johnson KR, Baillie GS, Karginov AV, Skidgel RA, O’Bryan JP, Carnegie GK (2015) UCR1C is a novel activator of phosphodiesterase 4 (PDE4) long isoforms and attenuates cardiomyocyte hypertrophy. Cell Signal 27(5):908–922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Willis MJ, Baillie GS (2014) Arrestin-dependent localization of phosphodiesterases. Handb Exp Pharmacol 219:293–307

    Article  CAS  PubMed  Google Scholar 

  • Wilson LS, Baillie GS, Pritchard LM, Umana B, Terrin A, Zaccolo M, Houslay MD, Maurice DH (2011) A phosphodiesterase 3B-based signaling complex integrates exchange protein activated by cAMP 1 and phosphatidylinositol 3-kinase signals in human arterial endothelial cells. J Biol Chem 286(18):16285–16296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Woodrum D, Pipkin W, Tessier D, Komalavilas P, Brophy CM (2003) Phosphorylation of the heat shock-related protein, HSP20, mediates cyclic nucleotide-dependent relaxation. J Vasc Surg 37(4):874–881

    Article  PubMed  Google Scholar 

Download references

Compliance with Ethical Standards

Conflict of Interest Statement

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Institute of Cardiovascular and Medical Sciences, College of Veterinary Medical and Life Sciences, Glasgow University, Glasgow, G128QQ, UK

    Lauren Wills, Bracy A. Fertig & George S. Baillie

Authors
  1. Lauren Wills
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bracy A. Fertig
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. George S. Baillie
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Institute of Experimental Cardiovascular Research, University Medical Center, Hamburg-Eppendorf, Germany

    Viacheslav Nikolaev

  2. Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK

    Manuela Zaccolo

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Wills, L., Fertig, B.A., Baillie, G.S. (2017). Cardiac cAMP Microdomains and Their Modulation Using Disruptor Peptides. In: Nikolaev, V., Zaccolo, M. (eds) Microdomains in the Cardiovascular System. Cardiac and Vascular Biology, vol 3. Springer, Cham. https://doi.org/10.1007/978-3-319-54579-0_9

Download citation

Publish with us

Policies and ethics

Search

Navigation