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Receptor-Cyclic Nucleotide Microdomains in the Heart

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Microdomains in the Cardiovascular System

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

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Abstract

Cyclic nucleotides 3′,5′-cyclic adenosine (cAMP) and 3′,5′-cyclic guanosine monophosphates (cGMP) are important second messengers which regulate cardiac function and disease by acting in spatially separated subcellular microdomains. Function of these microdomains includes but is not limited to the modulation of calcium cycling, excitation-contraction coupling, and cardiac hypertrophy. In recent years, visualization of local compartmentalized cAMP and cGMP dynamics became possible due to rapid development of optical and nonoptical imaging techniques. In this chapter, we will briefly review these state-of-the-art biophysical methods and available fluorescent biosensors which can be used to understand microdomain-specific signaling and its involvement in cardiovascular function and disease.

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Abbreviations

cAMP:

3′,5′-Cyclic adenosine monophosphate

CM:

Cardiomyocyte

CFP:

Cyan fluorescent protein

cGMP:

3′,5′-Cyclic guanosine monophosphate

FRET:

Förster resonance energy transfer

GFP:

Green fluorescent protein

IBMX:

3-Isobutyl-1-methylxanthine

ISO:

Isoproterenol

PDE:

Phosphodiesterase

PLN:

Phospholamban

SICM:

Scanning ion conductance microscopy

SR:

Sarcoplasmic reticulum

YFP:

Yellow fluorescent protein

β-AR:

β-Adrenergic receptor

References

  • Adams SR, Harootunian AT, Buechler YJ et al (1991) Fluorescence ratio imaging of cyclic AMP in single cells. Nature 349:694–697

    Article  CAS  PubMed  Google Scholar 

  • Allen MD, Zhang J (2006) Subcellular dynamics of protein kinase a activity visualized by FRET-based reporters. Biochem Biophys Res Commun 348:716–721

    Article  CAS  PubMed  Google Scholar 

  • Ashman DF, Lipton R, Melicow MM et al (1963) Isolation of adenosine 3′, 5′-monophosphate and guanosine 3′, 5′-monophosphate from rat urine. Biochem Biophys Res Commun 11:330–334

    Article  CAS  PubMed  Google Scholar 

  • Beavo JA, Brunton LL (2002) Cyclic nucleotide research—still expanding after half a century. Nat Rev Mol Cell Biol 3:710–718

    Article  CAS  PubMed  Google Scholar 

  • Belge C, Hammond J, Dubois-Deruy E et al (2014) Enhanced expression of beta3-adrenoceptors in cardiac myocytes attenuates neurohormone-induced hypertrophic remodeling through nitric oxide synthase. Circulation 129:451–462

    Article  CAS  PubMed  Google Scholar 

  • Bers DM (2002) Cardiac excitation-contraction coupling. Nature 415:198–205

    Article  CAS  PubMed  Google Scholar 

  • Bhargava Y, Hampden-Smith K, Chachlaki K et al (2013) Improved genetically-encoded, FlincG-type fluorescent biosensors for neural cGMP imaging. Front Mol Neurosci 6:26

    Article  PubMed  PubMed Central  Google Scholar 

  • Brodde OE, Bruck H, Leineweber K (2006) Cardiac adrenoceptors: physiological and pathophysiological relevance. J Pharmacol Sci 100:323–337

    Article  CAS  PubMed  Google Scholar 

  • Brooker G, Harper JF, Terasaki WL et al (1979) Radioimmunoassay of cyclic AMP and cyclic GMP. Adv Cyclic Nucleotide Res 10:1–33

    CAS  PubMed  Google Scholar 

  • Buxton IL, Brunton LL (1983) Compartments of cyclic AMP and protein kinase in mammalian cardiomyocytes. J Biol Chem 258:10233–10239

    Article  CAS  PubMed  Google Scholar 

  • Calebiro D, Nikolaev VO, Gagliani MC et al (2009) Persistent cAMP-signals triggered by internalized G-protein-coupled receptors. PLoS Biol 7:e1000172

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Castro LR, Gervasi N, Guiot E et al (2010) Type 4 phosphodiesterase plays different integrating roles in different cellular domains in pyramidal cortical neurons. J Neurosci 30:6143–6151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Couto A, Oda S, Nikolaev VO et al (2013) In vivo genetic dissection of O2-evoked cGMP dynamics in a Caenorhabditis elegans gas sensor. Proc Natl Acad Sci U S A 110:E3301–E3310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De Arcangelis V, Liu R, Soto D et al (2009) Differential association of phosphodiesterase 4D isoforms with beta2-adrenoceptor in cardiac myocytes. J Biol Chem 284:33824–33832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Depry C, Allen MD, Zhang J (2011) Visualization of PKA activity in plasma membrane microdomains. Mol Biosyst 7:52–58

    Article  CAS  PubMed  Google Scholar 

  • Di Benedetto G, Zoccarato A, Lissandron V et al (2008) Protein kinase a type I and type II define distinct intracellular signaling compartments. Circ Res 103:836–844

    Article  CAS  PubMed  Google Scholar 

  • DiPilato LM, Cheng X, Zhang J (2004) Fluorescent indicators of cAMP and Epac activation reveal differential dynamics of cAMP signaling within discrete subcellular compartments. Proc Natl Acad Sci U S A 101:16513–16518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dyachok O, Isakov Y, Sagetorp J et al (2006) Oscillations of cyclic AMP in hormone-stimulated insulin-secreting beta-cells. Nature 439:349–352

    Article  CAS  PubMed  Google Scholar 

  • Fischmeister R, Castro LR, Abi-Gerges A et al (2006) Compartmentation of cyclic nucleotide signaling in the heart: the role of cyclic nucleotide phosphodiesterases. Circ Res 99:816–828

    Article  CAS  PubMed  Google Scholar 

  • Froese A, Nikolaev VO (2015) Imaging alterations of cardiomyocyte cAMP microdomains in disease. Front Pharmacol 6:172

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fu Q, Kim S, Soto D et al (2014) A long lasting beta1 adrenergic receptor stimulation of cAMP/protein kinase a (PKA) signal in cardiac myocytes. J Biol Chem 289:14771–14781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Götz KR, Sprenger JU, Perera RK et al (2014) Transgenic mice for real-time visualization of cGMP in intact adult cardiomyocytes. Circ Res 114:1235–1245

    Article  PubMed  CAS  Google Scholar 

  • Haj Slimane Z, Bedioune I, Lechene P et al (2014) Control of cytoplasmic and nuclear protein kinase a by phosphodiesterases and phosphatases in cardiac myocytes. Cardiovasc Res 102:97–106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hansma PK, Drake B, Marti O et al (1989) The scanning ion-conductance microscope. Science 243:641–643

    Article  CAS  PubMed  Google Scholar 

  • Hayes JS, Brunton LL, Mayer SE (1980) Selective activation of particulate cAMP-dependent protein kinase by isoproterenol and prostaglandin E1. J Biol Chem 255:5113–5119

    Article  CAS  PubMed  Google Scholar 

  • Herbst KJ, Coltharp C, Amzel LM et al (2011) Direct activation of Epac by sulfonylurea is isoform selective. Chem Biol 18:243–251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Herget S, Lohse MJ, Nikolaev VO (2008) Real-time monitoring of phosphodiesterase inhibition in intact cells. Cell Signal 20:1423–1431

    Article  CAS  PubMed  Google Scholar 

  • Honda A, Adams SR, Sawyer CL et al (2001) Spatiotemporal dynamics of guanosine 3',5'-cyclic monophosphate revealed by a genetically encoded, fluorescent indicator. Proc Natl Acad Sci U S A 98:2437–2442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klarenbeek J, Goedhart J, van Batenburg A et al (2015) Fourth-generation Epac-based FRET sensors for cAMP feature exceptional brightness, photostability and dynamic range: characterization of dedicated sensors for FLIM, for ratiometry and with high affinity. PLoS One 10:e0122513

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Korchev YE, Bashford CL, Milovanovic M et al (1997) Scanning ion conductance microscopy of living cells. Biophys J 73:653–658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu S, Zhang J, Xiang YK (2011) FRET-based direct detection of dynamic protein kinase a activity on the sarcoplasmic reticulum in cardiomyocytes. Biochem Biophys Res Commun 404:581–586

    Article  CAS  PubMed  Google Scholar 

  • Lohse MJ, Engelhardt S, Eschenhagen T (2003) What is the role of beta-adrenergic signaling in heart failure? Circ Res 93:896–906

    Article  CAS  PubMed  Google Scholar 

  • Lompre AM, Hajjar RJ, Harding SE et al (2010) Ca2+ cycling and new therapeutic approaches for heart failure. Circulation 121:822–830

    Article  PubMed  PubMed Central  Google Scholar 

  • Mehta S, Aye-Han NN, Ganesan A et al (2014) Calmodulin-controlled spatial decoding of oscillatory Ca2+ signals by calcineurin. Elife 3:e03765

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mohamed TM, Oceandy D, Zi M et al (2011) Plasma membrane calcium pump (PMCA4)-neuronal nitric-oxide synthase complex regulates cardiac contractility through modulation of a compartmentalized cyclic nucleotide microdomain. J Biol Chem 286:41520–41529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mongillo M, McSorley T, Evellin S et al (2004) Fluorescence resonance energy transfer-based analysis of cAMP dynamics in live neonatal rat cardiac myocytes reveals distinct functions of compartmentalized phosphodiesterases. Circ Res 95:67–75

    Article  CAS  PubMed  Google Scholar 

  • Mukherjee S, Jansen V, Jikeli JF et al (2016) A novel biosensor to study cAMP dynamics in cilia and flagella. Elife 5

    Google Scholar 

  • Nausch LW, Ledoux J, Bonev AD et al (2008) Differential patterning of cGMP in vascular smooth muscle cells revealed by single GFP-linked biosensors. Proc Natl Acad Sci U S A 105:365–370

    Article  CAS  PubMed  Google Scholar 

  • Niino Y, Hotta K, Oka K (2009) Simultaneous live cell imaging using dual FRET sensors with a single excitation light. PLoS One 4:e6036

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nikolaev VO, Bunemann M, Hein L et al (2004) Novel single chain cAMP sensors for receptor-induced signal propagation. J Biol Chem 279:37215–37218

    Article  CAS  PubMed  Google Scholar 

  • Nikolaev VO, Bunemann M, Schmitteckert E et al (2006a) Cyclic AMP imaging in adult cardiac myocytes reveals far-reaching beta1-adrenergic but locally confined beta2-adrenergic receptor-mediated signaling. Circ Res 99:1084–1091

    Article  CAS  PubMed  Google Scholar 

  • Nikolaev VO, Gambaryan S, Lohse MJ (2006b) Fluorescent sensors for rapid monitoring of intracellular cGMP. Nat Methods 3:23–25

    Article  CAS  PubMed  Google Scholar 

  • Nikolaev VO, Moshkov A, Lyon AR et al (2010) Beta2-adrenergic receptor redistribution in heart failure changes cAMP compartmentation. Science 327:1653–1657

    Article  CAS  PubMed  Google Scholar 

  • Norris RP, Ratzan WJ, Freudzon M et al (2009) Cyclic GMP from the surrounding somatic cells regulates cyclic AMP and meiosis in the mouse oocyte. Development 136:1869–1878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perera RK, Nikolaev VO (2013) Compartmentation of cAMP signalling in cardiomyocytes in health and disease. Acta Physiol (Oxf) 207:650–662

    Article  CAS  Google Scholar 

  • Perera RK, Sprenger JU, Steinbrecher JH et al (2015) Microdomain switch of cGMP-regulated phosphodiesterases leads to ANP-induced augmentation of beta-adrenoceptor-stimulated contractility in early cardiac hypertrophy. Circ Res 116:1304–1311

    Article  CAS  PubMed  Google Scholar 

  • Ponsioen B, Zhao J, Riedl J et al (2004) Detecting cAMP-induced Epac activation by fluorescence resonance energy transfer: Epac as a novel cAMP indicator. EMBO Rep 5:1176–1180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Richter W, Mika D, Blanchard E et al (2013) beta1-adrenergic receptor antagonists signal via PDE4 translocation. EMBO Rep 14:276–283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Russwurm M, Mullershausen F, Friebe A et al (2007) Design of fluorescence resonance energy transfer (FRET)-based cGMP indicators: a systematic approach. Biochem J 407:69–77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sato M, Hida N, Ozawa T et al (2000) Fluorescent indicators for cyclic GMP based on cyclic GMP-dependent protein kinase I alpha and green fluorescent proteins. Anal Chem 72:5918–5924

    Article  CAS  PubMed  Google Scholar 

  • Shafer OT, Kim DJ, Dunbar-Yaffe R et al (2008) Widespread receptivity to neuropeptide PDF throughout the neuronal circadian clock network of drosophila revealed by real-time cyclic AMP imaging. Neuron 58:223–237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sin YY, Edwards HV, Li X et al (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 50:872–883

    Article  CAS  PubMed  Google Scholar 

  • Sprenger JU, Nikolaev VO (2013) Biophysical techniques for detection of cAMP and cGMP in living cells. Int J Mol Sci 14:8025–8046

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sprenger JU, Perera RK, Steinbrecher JH et al (2015) In vivo model with targeted cAMP biosensor reveals changes in receptor-microdomain communication in cardiac disease. Nat Commun 6:6965

    Article  CAS  PubMed  Google Scholar 

  • Stangherlin A, Gesellchen F, Zoccarato A et al (2011) cGMP signals modulate cAMP levels in a compartment-specific manner to regulate catecholamine-dependent signaling in cardiac myocytes. Circ Res 108:929–939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sutherland EW, Rall TW (1958) Fractionation and characterization of a cyclic adenine ribonucleotide formed by tissue particles. J Biol Chem 232:1077–1091

    Article  CAS  PubMed  Google Scholar 

  • Tao W, Rubart M, Ryan J et al (2015) A practical method for monitoring FRET-based biosensors in living animals using two-photon microscopy. Am J Physiol Cell Physiol 309:C724–C735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thunemann M, Wen L, Hillenbrand M et al (2013) Transgenic mice for cGMP imaging. Circ Res 113:365–371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Violin JD, DiPilato LM, Yildirim N et al (2008) beta2-adrenergic receptor signaling and desensitization elucidated by quantitative modeling of real time cAMP dynamics. J Biol Chem 283:2949–2961

    Article  CAS  PubMed  Google Scholar 

  • Wachten S, Masada N, Ayling LJ et al (2010) Distinct pools of cAMP Centre on different isoforms of adenylyl cyclase in pituitary-derived GH3B6 cells. J Cell Sci 123:95–106

    Article  CAS  PubMed  Google Scholar 

  • Warrier S, Belevych AE, Ruse M et al (2005) Beta-adrenergic- and muscarinic receptor-induced changes in cAMP activity in adult cardiac myocytes detected with FRET-based biosensor. Am J Physiol Cell Physiol 289:C455–C461

    Article  CAS  PubMed  Google Scholar 

  • Williams C (2004) cAMP detection methods in HTS: selecting the best from the rest. Nat Rev Drug Discov 3:125–135

    Article  CAS  PubMed  Google Scholar 

  • Zaccolo M (2004) Use of chimeric fluorescent proteins and fluorescence resonance energy transfer to monitor cellular responses. Circ Res 94:866–873

    Article  CAS  PubMed  Google Scholar 

  • Zaccolo M (2009) cAMP signal transduction in the heart: understanding spatial control for the development of novel therapeutic strategies. Br J Pharmacol 158:50–60

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zaccolo M, De Giorgi F, Cho CY et al (2000) A genetically encoded, fluorescent indicator for cyclic AMP in living cells. Nat Cell Biol 2:25–29

    Article  CAS  PubMed  Google Scholar 

  • Zaccolo M, Pozzan T (2002) Discrete microdomains with high concentration of cAMP in stimulated rat neonatal cardiac myocytes. Science 295:1711–1715

    Article  CAS  PubMed  Google Scholar 

  • Zhang CL, Katoh M, Shibasaki T et al (2009) The cAMP sensor Epac2 is a direct target of antidiabetic sulfonylurea drugs. Science 325:607–610

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Campbell RE, Ting AY et al (2002) Creating new fluorescent probes for cell biology. Nat Rev Mol Cell Biol 3:906–918

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Hupfeld CJ, Taylor SS et al (2005) Insulin disrupts beta-adrenergic signalling to protein kinase a in adipocytes. Nature 437:569–573

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Ma Y, Taylor SS et al (2001) Genetically encoded reporters of protein kinase a activity reveal impact of substrate tethering. Proc Natl Acad Sci U S A 98:14997–15002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgment

The work in authors’ laboratory is supported by the grants from the German Research Foundation (“Deutsche Forschungsgemeinschaft” grants NI 1301/1, NI 1301/2, FOR 2060) and by the Gertraud und Heinz-Rose Stiftung.

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Conflict of Interest Statement

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany

    Nadja I. Bork & Viacheslav O. Nikolaev

  2. DZHK (German Center for Cardiovascular Research) Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany

    Nadja I. Bork & Viacheslav O. Nikolaev

Authors
  1. Nadja I. Bork
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  2. Viacheslav O. Nikolaev
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Correspondence to Viacheslav O. Nikolaev .

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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

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Bork, N.I., Nikolaev, V.O. (2017). Receptor-Cyclic Nucleotide Microdomains in the Heart. 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_1

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