Skip to main content
SpringerLink
Log in

Heart failure-specific changes in protein kinase signalling

  • Invited Review
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Among the myriad of molecular alterations occurring in heart failure development, aggravation of the disease is often attributed to global or local changes in protein kinase activity, thus making protein kinases attractive targets for therapeutic intervention. Since protein kinases do not only have maladaptive roles, but also contribute to the physiological integrity of cells, it is a challenging task to circumvent undesired inhibition of protein kinase activity. Identification of posttranslational modifications and/or protein-protein interactions that are exclusively apparent under pathophysiological conditions provides exciting information for alternative non-kinase inhibitory treatment strategies that eliminate maladaptive functions of a protein kinase, but preserve the beneficial ones. Here, we focus on the disease-specific regulation of a number of protein kinases, namely, Ca2+/calmodulin-dependent protein kinase II isoform δ (CaMKIIδ), G protein-coupled receptor kinase 2 (GRK2), extracellular signal-regulated kinase 1 and 2 (ERK1/2), protein kinase D (PKD) and protein kinase C isoform β2 (PKCβ2), which are embedded in complex signal transduction pathways implicated in heart failure development, and discuss potential avenues for novel treatment strategies to combat heart disease.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

AKAP:

A-kinase-anchoring protein

AKAP-Lbc:

A-kinase-anchoring protein lymphoid blast crisis oncogene

βARKct:

β-Adrenergic receptor kinase C-terminus

β1AR:

β1-Adrenergic receptor

CaMK:

Ca2+/calmodulin-dependent protein kinase

ERK:

Extracellular signal-regulated kinase

FHL:

Four-and-a-half LIM domains

GPCR:

G protein-coupled receptor

Gβγ:

G protein βγ subunits

GRK:

G protein-coupled receptor kinase

HF:

Heart failure

HDAC:

Histone deacetylase

IQGAP:

IQ motif-containing GTPase-activating protein

I-1:

Inhibitor isoform 1

mAKAP:

Muscle-specific A-kinase-anchoring protein

MAPK:

Mitogen-activated protein kinase

MEF2:

Myocyte enhancer factor 2

OPTM:

Oxidative posttranslational modification

PTM:

Posttranslational modifications

PDE:

Phosphodiesterase

PKA:

cAMP-dependent protein kinase

PKD:

Protein kinase D

PKC:

Protein kinase C

PP-1:

Protein phosphatase type 1

ROS:

Reactive oxygen species

RACK:

Receptor for activated C-kinase

References

  1. Ahn S, Shenoy SK, Wei H, Lefkowitz RJ (2004) Differential kinetic and spatial patterns of β-arrestin and G protein-mediated ERK activation by the angiotensin II receptor. J Biol Chem 279:35518–35525

    CAS  PubMed  Google Scholar 

  2. Ai X, Curran JW, Shannon TR, Bers DM, Pogwizd SM (2005) Ca2+/calmodulin-dependent protein kinase modulates cardiac ryanodine receptor phosphorylation and sarcoplasmic reticulum Ca2+ leak in heart failure. Circ Res 97:1314–1322

    CAS  PubMed  Google 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 100:4445–4450

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Arya R, Kedar V, Hwang JR, McDonough H, Li HH, Taylor J, Patterson C (2004) Muscle ring finger protein-1 inhibits PKCε activation and prevents cardiomyocyte hypertrophy. J Cell Biol 167:1147–1159

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Backs J, Backs T, Neef S, Kreusser MM, Lehmann LH, Patrick DM, Grueter CE, Qi X, Richardson JA, Hill JA, Katus HA, Bassel-Duby R, Maier LS, Olson EN (2009) The δ isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload. Proc Natl Acad Sci U S A 106:2342–2347

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Backs J, Song K, Bezprozvannaya S, Chang S, Olson EN (2006) CaM kinase II selectively signals to histone deacetylase 4 during cardiomyocyte hypertrophy. J Clin Invest 116:1853–1864

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Bates E, Bode C, Costa M, Gibson CM, Granger C, Green C, Grimes K, Harrington R, Huber K, Kleiman N, Mochly-Rosen D, Roe M, Sadowski Z, Solomon S, Widimsky P (2008) Intracoronary KAI-9803 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction. Circulation 117:886–896

    PubMed  Google Scholar 

  8. Bathgate-Siryk A, Dabul S, Pandya K, Walklett K, Rengo G, Cannavo A, De Lucia C, Liccardo D, Gao E, Leosco D, Koch WJ, Lymperopoulos A (2014) Negative impact of β-arrestin-1 on post-myocardial infarction heart failure via cardiac and adrenal-dependent neurohormonal mechanisms. Hypertension 63:404–412

    CAS  PubMed  Google Scholar 

  9. Belmonte SL, Blaxall BC (2011) G protein coupled receptor kinases as therapeutic targets in cardiovascular disease. Circ Res 109:309–319

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Bossuyt J, Helmstadter K, Wu X, Clements-Jewery H, Haworth RS, Avkiran M, Martin JL, Pogwizd SM, Bers DM (2008) Ca2+/calmodulin-dependent protein kinase IIδ and protein kinase D overexpression reinforce the histone deacetylase 5 redistribution in heart failure. Circ Res 102:695–702

    CAS  PubMed  Google Scholar 

  11. Bovill E, Westaby S, Crisp A, Jacobs S, Shaw T (2009) Reduction of four-and-a-half LIM-protein 2 expression occurs in human left ventricular failure and leads to altered localization and reduced activity of metabolic enzymes. J Thorac Cardiovasc Surg 137:853–861

    CAS  PubMed  Google Scholar 

  12. Bowling N, Walsh RA, Song G, Estridge T, Sandusky GE, Fouts RL, Mintze K, Pickard T, Roden R, Bristow MR, Sabbah HN, Mizrahi JL, Gromo G, King GL, Vlahos CJ (1999) Increased protein kinase C activity and expression of Ca2+-sensitive isoforms in the failing human heart. Circulation 99:384–391

    CAS  PubMed  Google Scholar 

  13. Boyle AJ, Kelly DJ, Zhang Y, Cox AJ, Gow RM, Way K, Itescu S, Krum H, Gilbert RE (2005) Inhibition of protein kinase C reduces left ventricular fibrosis and dysfunction following myocardial infarction. J Mol Cell Cardiol 39:213–221

    CAS  PubMed  Google Scholar 

  14. Bristow MR, Ginsburg R, Minobe W, Cubicciotti RS, Sageman WS, Lurie K, Billingham ME, Harrison DC, Stinson EB (1982) Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts. N Engl J Med 307:205–211

    Google Scholar 

  15. Brown MD, Sacks DB (2009) Protein scaffolds in MAP kinase signalling. Cell Signal 21:462–469

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Cannavo A, Liccardo D, Koch WJ (2013) Targeting cardiac β-adrenergic signaling via GRK2 inhibition for heart failure therapy. Front Physiol 4:264

    PubMed Central  PubMed  Google Scholar 

  17. 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 281:21535–21545

    CAS  PubMed  Google Scholar 

  18. Carnegie GK, Burmeister BT (2011) A-kinase anchoring proteins that regulate cardiac remodeling. J Cardiovasc Pharmacol 58:451–458

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Carnegie GK, Means CK, Scott JD (2009) A-kinase anchoring proteins: from protein complexes to physiology and disease. IUBMB Life 61:394–406

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Casey LM, Pistner AR, Belmonte SL, Migdalovich D, Stolpnik O, Nwakanma FE, Vorobiof G, Dunaevsky O, Matavel A, Lopes CM, Smrcka AV, Blaxall BC (2010) Small molecule disruption of Gβγ signaling inhibits the progression of heart failure. Circ Res 107:532–539

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Chen G, Zhou X, Florea S, Qian J, Cai W, Zhang Z, Fan GC, Lorenz J, Hajjar RJ, Kranias EG (2010) Expression of active protein phosphatase 1 inhibitor-1 attenuates chronic beta-agonist-induced cardiac apoptosis. Basic Res Cardiol 105:573–581

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Chen S, Spiegelberg BD, Lin F, Dell EJ, Hamm HE (2004) Interaction of Gβγ with RACK1 and other WD40 repeat proteins. J Mol Cell Cardiol 37:399–406

    CAS  PubMed  Google Scholar 

  23. Cheng H, Kari G, Dicker AP, Rodeck U, Koch WJ, Force T (2011) A novel preclinical strategy for identifying cardiotoxic kinase inhibitors and mechanisms of cardiotoxicity. Circ Res 109:1401–1409

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Choi DJ, Koch WJ, Hunter JJ, Rockman HA (1997) Mechanism of β-adrenergic receptor desensitization in cardiac hypertrophy is increased β-adrenergic receptor kinase. J Biol Chem 272:17223–17229

    CAS  PubMed  Google Scholar 

  25. Chu PH, Bardwell WM, Gu Y, Ross J Jr, Chen J (2000) FHL2 (SLIM3) is not essential for cardiac development and function. Mol Cell Biol 20:7460–7462

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Chu PH, Chen J (2011) The novel roles of four and a half LIM proteins 1 and 2 in the cardiovascular system. Chang Gung Med J 34:127–134

    PubMed  Google Scholar 

  27. Cohen P (2002) The origins of protein phosphorylation. Nat Cell Biol 4:E127–E130

    CAS  PubMed  Google Scholar 

  28. Dodge-Kafka KL, Soughayer J, Pare GC, Carlisle Michel JJ, Langeberg LK, Kapiloff MS, Scott JD (2005) The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways. Nature 437:574–578

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Dzimiri N, Muiya P, Andres E, Al-Halees Z (2004) Differential functional expression of human myocardial G protein receptor kinases in left ventricular cardiac diseases. Eur J Pharmacol 489:167–177

    CAS  PubMed  Google Scholar 

  30. Eishingdrelo H, Kongsamut S (2013) Minireview: targeting GPCR activated ERK pathways for drug discovery. Curr Chem Genomics Transl Med 7:9–15

    PubMed Central  PubMed  Google Scholar 

  31. El-Armouche A, Eschenhagen T (2009) β-adrenergic stimulation and myocardial function in the failing heart. Heart Fail Rev 14:225–241

    CAS  PubMed  Google Scholar 

  32. Erickson JR, Joiner ML, Guan X, Kutschke W, Yang J, Oddis CV, Bartlett RK, Lowe JS, O’Donnell SE, Aykin-Burns N, Zimmerman MC, Zimmerman K, Ham AJ, Weiss RM, Spitz DR, Shea MA, Colbran RJ, Mohler PJ, Anderson ME (2008) A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation. Cell 133:462–474

    CAS  PubMed Central  PubMed  Google Scholar 

  33. Erickson JR, Pereira L, Wang L, Han G, Ferguson A, Dao K, Copeland RJ, Despa F, Hart GW, Ripplinger CM, Bers DM (2013) Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation. Nature 502:372–376

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Esseltine JL, Scott JD (2013) AKAP signaling complexes: pointing towards the next generation of therapeutic targets? Trends Pharmacol Sci 34:648–655

    CAS  PubMed  Google Scholar 

  35. Ferguson BS, Harrison BC, Jeong MY, Reid BG, Wempe MF, Wagner FF, Holson EB, McKinsey TA (2013) Signal-dependent repression of DUSP5 by class I HDACs controls nuclear ERK activity and cardiomyocyte hypertrophy. Proc Natl Acad Sci U S A 110:9806–9811

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Ferreira JC, Boer BN, Grinberg M, Brum PC, Mochly-Rosen D (2012) Protein quality control disruption by PKCβII in heart failure; rescue by the selective PKCβII inhibitor, βIIV5-3. PLoS One 7:e33175

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Ferreira JC, Brum PC, Mochly-Rosen D (2011) βIIPKC and εPKC isozymes as potential pharmacological targets in cardiac hypertrophy and heart failure. J Mol Cell Cardiol 51:479–484

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Fielitz J, Kim MS, Shelton JM, Qi X, Hill JA, Richardson JA, Bassel-Duby R, Olson EN (2008) Requirement of protein kinase D1 for pathological cardiac remodeling. Proc Natl Acad Sci U S A 105:3059–3063

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Fimia GM, De Cesare D, Sassone-Corsi P (2000) A family of LIM-only transcriptional coactivators: tissue-specific expression and selective activation of CREB and CREM. Mol Cell Biol 20:8613–8622

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Fischer TH, Herting J, Tirilomis T, Renner A, Neef S, Toischer K, Ellenberger D, Forster A, Schmitto JD, Gummert J, Schondube FA, Hasenfuss G, Maier LS, Sossalla S (2013) Ca2+/calmodulin-dependent protein kinase II and protein kinase A differentially regulate sarcoplasmic reticulum Ca2+ leak in human cardiac pathology. Circulation 128:970–981

    CAS  PubMed  Google Scholar 

  41. Force T, Kolaja KL (2011) Cardiotoxicity of kinase inhibitors: the prediction and translation of preclinical models to clinical outcomes. Nat Rev Drug Discov 10:111–126

    CAS  PubMed  Google Scholar 

  42. Gros R, Benovic JL, Tan CM, Feldman RD (1997) G-protein-coupled receptor kinase activity is increased in hypertension. J Clin Invest 99:2087–2093

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Guo J, Cong L, Rybin VO, Gertsberg Z, Steinberg SF (2010) Protein kinase C-δ regulates the subcellular localization of Shc in H2O2-treated cardiomyocytes. Am J Physiol Cell Physiol 299:C770–C778

    CAS  PubMed Central  PubMed  Google Scholar 

  44. Gurevich EV, Tesmer JJ, Mushegian A, Gurevich VV (2012) G protein-coupled receptor kinases: more than just kinases and not only for GPCRs. Pharmacol Ther 133:40–69

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Hafstad AD, Nabeebaccus AA, Shah AM (2013) Novel aspects of ROS signalling in heart failure. Basic Res Cardiol 108:359

    PubMed  Google Scholar 

  46. Harrison BC, Kim MS, van Rooij E, Plato CF, Papst PJ, Vega RB, McAnally JA, Richardson JA, Bassel-Duby R, Olson EN, McKinsey TA (2006) Regulation of cardiac stress signaling by protein kinase d1. Mol Cell Biol 26:3875–3888

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Hata JA, Williams ML, Koch WJ (2004) Genetic manipulation of myocardial β-adrenergic receptor activation and desensitization. J Mol Cell Cardiol 37:11–21

    CAS  PubMed  Google Scholar 

  48. Heineke J, Molkentin JD (2006) Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol 7:589–600

    CAS  PubMed  Google Scholar 

  49. Hoch B, Meyer R, Hetzer R, Krause EG, Karczewski P (1999) Identification and expression of δ-isoforms of the multifunctional Ca2+/calmodulin-dependent protein kinase in failing and nonfailing human myocardium. Circ Res 84:713–721

    CAS  PubMed  Google Scholar 

  50. Hudmon A, Schulman H (2002) Structure-function of the multifunctional Ca2+/calmodulin-dependent protein kinase II. Biochem J 364:593–611

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Ikeda SR (1996) Voltage-dependent modulation of N-type calcium channels by G-protein βγ subunits. Nature 380:255–258

    CAS  PubMed  Google Scholar 

  52. Inagaki K, Iwanaga Y, Sarai N, Onozawa Y, Takenaka H, Mochly-Rosen D, Kihara Y (2002) Tissue angiotensin II during progression or ventricular hypertrophy to heart failure in hypertensive rats; differential effects on PKCε and PKCβ. J Mol Cell Cardiol 34:1377–1385

    CAS  PubMed  Google Scholar 

  53. Ivanina T, Blumenstein Y, Shistik E, Barzilai R, Dascal N (2000) Modulation of L-type Ca2+ channels by Gβγ and calmodulin via interactions with N and C termini of α1C. J Biol Chem 275:39846–39854

    CAS  PubMed  Google Scholar 

  54. Johannessen M, Møller S, Hansen T, Moens U, Van Ghelue M (2006) The multifunctional roles of the four-and-a-half-LIM only protein FHL2. Cell Mol Life Sci 63:268–284

    CAS  PubMed  Google Scholar 

  55. Kamal FA, Smrcka AV, Blaxall BC (2011) Taking the heart failure battle inside the cell: small molecule targeting of Gβγ subunits. J Mol Cell Cardiol 51:462–467

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Kaneda H, Ikeno F, Inagaki K, Mochly-Rosen D (2009) Preserved coronary endothelial function by inhibition of δ protein kinase C in a porcine acute myocardial infarction model. Int J Cardiol 133:256–259

    PubMed Central  PubMed  Google Scholar 

  57. Kimura TE, Jin J, Zi M, Prehar S, Liu W, Oceandy D, Abe J, Neyses L, Weston AH, Cartwright EJ, Wang X (2010) Targeted deletion of the extracellular signal-regulated protein kinase 5 attenuates hypertrophic response and promotes pressure overload-induced apoptosis in the heart. Circ Res 106:961–970

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Kirchhefer U, Schmitz W, Scholz H, Neumann J (1999) Activity of cAMP-dependent protein kinase and Ca2+/calmodulin-dependent protein kinase in failing and nonfailing human hearts. Cardiovasc Res 42:254–261

    CAS  PubMed  Google Scholar 

  59. Koch WJ, Rockman HA, Samama P, Hamilton RA, Bond RA, Milano CA, Lefkowitz RJ (1995) Cardiac function in mice overexpressing the β-adrenergic receptor kinase or a βARK inhibitor. Science 268:1350–1353

    CAS  PubMed  Google Scholar 

  60. Komander D, Kular GS, Schuttelkopf AW, Deak M, Prakash KR, Bain J, Elliott M, Garrido-Franco M, Kozikowski AP, Alessi DR, van Aalten DM (2004) Interactions of LY333531 and other bisindolyl maleimide inhibitors with PDK1. Structure 12:215–226

    CAS  PubMed  Google Scholar 

  61. Kong Y, Shelton JM, Rothermel B, Li X, Richardson JA, Bassel-Duby R, Williams RS (2001) Cardiac-specific LIM protein FHL2 modifies the hypertrophic response to β-adrenergic stimulation. Circulation 103:2731–2738

    CAS  PubMed  Google Scholar 

  62. Lal H, Kolaja KL, Force T (2013) Cancer genetics and the cardiotoxicity of the therapeutics. J Am Coll Cardiol 61:267–274

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  64. Lefkowitz RJ, Rajagopal K, Whalen EJ (2006) New roles for β-arrestins in cell signaling: not just for seven-transmembrane receptors. Mol Cell 24:643–652

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Lim DS, Roberts R, Marian AJ (2001) Expression profiling of cardiac genes in human hypertrophic cardiomyopathy: insight into the pathogenesis of phenotypes. J Am Coll Cardiol 38:1175–1180

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Lin Y, Smrcka AV (2011) Understanding molecular recognition by G protein βγ subunits on the path to pharmacological targeting. Mol Pharmacol 80:551–557

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Ling H, Zhang T, Pereira L, Means CK, Cheng H, Gu Y, Dalton ND, Peterson KL, Chen J, Bers D, Brown JH (2009) Requirement for Ca2+/calmodulin-dependent kinase II in the transition from pressure overload-induced cardiac hypertrophy to heart failure in mice. J Clin Invest 119:1230–1240

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Logothetis DE, Kurachi Y, Galper J, Neer EJ, Clapham DE (1987) The βγ subunits of GTP-binding proteins activate the muscarinic K+ channel in heart. Nature 325:321–326

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  71. Lorenz K, Schmitt JP, Schmitteckert EM, Lohse MJ (2009) A new type of ERK1/2 autophosphorylation causes cardiac hypertrophy. Nat Med 15:75–83

    CAS  PubMed  Google Scholar 

  72. Lorenz K, Schmitt JP, Vidal M, Lohse MJ (2009) Cardiac hypertrophy: targeting Raf/MEK/ERK1/2-signaling. Int J Biochem Cell Biol 41:2351–2355

    CAS  PubMed  Google Scholar 

  73. Luttrell LM (2005) Composition and function of G protein-coupled receptor signalsomes controlling mitogen-activated protein kinase activity. J Mol Neurosci 26:253–264

    CAS  PubMed  Google Scholar 

  74. Lymperopoulos A, Negussie S (2013) βArrestins in cardiac G protein-coupled receptor signaling and function: partners in crime or "Good Cop, Bad Cop"? Int J Mol Sci 14:24726–24741

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Mangmool S, Shukla AK, Rockman HA (2010) β-Arrestin-dependent activation of Ca2+/calmodulin kinase II after β1-adrenergic receptor stimulation. J Cell Biol 189:573–587

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Marks AR (2013) Calcium cycling proteins and heart failure: mechanisms and therapeutics. J Clin Invest 123:46–52

    CAS  PubMed Central  PubMed  Google Scholar 

  77. 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 

  78. Maurice JP, Shah AS, Kypson AP, Hata JA, White DC, Glower DD, Koch WJ (1999) Molecular β-adrenergic signaling abnormalities in failing rabbit hearts after infarction. Am J Physiol 276:H1853–H1860

    CAS  PubMed  Google Scholar 

  79. 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

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Mochly-Rosen D, Miller KG, Scheller RH, Khaner H, Lopez J, Smith BL (1992) p65 fragments, homologous to the C2 region of protein kinase C, bind to the intracellular receptors for protein kinase C. Biochemistry 31:8120–8124

    CAS  PubMed  Google Scholar 

  81. Murphy BJ, Scott JD (1998) Functional anchoring of the cAMP-dependent protein kinase. Trends Cardiovasc Med 8:89–95

    CAS  PubMed  Google Scholar 

  82. Naga Prasad SV, Esposito G, Mao L, Koch WJ, Rockman HA (2000) Gβγ-dependent phosphoinositide 3-kinase activation in hearts with in vivo pressure overload hypertrophy. J Biol Chem 275:4693–4698

    CAS  PubMed  Google Scholar 

  83. Nicolaou P, Rodriguez P, Ren X, Zhou X, Qian J, Sadayappan S, Mitton B, Pathak A, Robbins J, Hajjar RJ, Jones K, Kranias EG (2009) Inducible expression of active protein phosphatase-1 inhibitor-1 enhances basal cardiac function and protects against ischemia/reperfusion injury. Circ Res 104:1012–1020

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Nienaber JJ, Tachibana H, Naga Prasad SV, Esposito G, Wu D, Mao L, Rockman HA (2003) Inhibition of receptor-localized PI3K preserves cardiac β-adrenergic receptor function and ameliorates pressure overload heart failure. J Clin Invest 112:1067–1079

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Oudit GY, Penninger JM (2009) Cardiac regulation by phosphoinositide 3-kinases and PTEN. Cardiovasc Res 82:250–260

    CAS  PubMed  Google Scholar 

  86. Pass JM, Gao J, Jones WK, Wead WB, Wu X, Zhang J, Baines CP, Bolli R, Zheng YT, Joshua IG, Ping P (2001) Enhanced PKCβII translocation and PKCβII-RACK1 interactions in PKCε-induced heart failure: a role for RACK1. Am J Physiol Heart Circ Physiol 281:H2500–H2510

    CAS  PubMed  Google Scholar 

  87. Pass JM, Zheng Y, Wead WB, Zhang J, Li RC, Bolli R, Ping P (2001) PKCε activation induces dichotomous cardiac phenotypes and modulates PKCε-RACK interactions and RACK expression. Am J Physiol Heart Circ Physiol 280:H946–H955

    CAS  PubMed  Google Scholar 

  88. Pathak A, del Monte F, Zhao W, Schultz JE, Lorenz JN, Bodi I, Weiser D, Hahn H, Carr AN, Syed F, Mavila N, Jha L, Qian J, Marreez Y, Chen G, McGraw DW, Heist EK, Guerrero JL, DePaoli-Roach AA, Hajjar RJ, Kranias EG (2005) Enhancement of cardiac function and suppression of heart failure progression by inhibition of protein phosphatase 1. Circ Res 96:756–766

    CAS  PubMed  Google Scholar 

  89. Penela P, Murga C, Ribas C, Lafarga V, Mayor F Jr (2010) The complex G protein-coupled receptor kinase 2 (GRK2) interactome unveils new physiopathological targets. Br J Pharmacol 160:821–832

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Perino A, Ghigo A, Scott JD, Hirsch E (2012) Anchoring proteins as regulators of signaling pathways. Circ Res 111:482–492

    CAS  PubMed Central  PubMed  Google Scholar 

  91. 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 β2-adrenergic receptors by β-arrestins. Science 298:834–836

    CAS  PubMed  Google Scholar 

  92. Pitcher JA, Inglese J, Higgins JB, Arriza JL, Casey PJ, Kim C, Benovic JL, Kwatra MM, Caron MG, Lefkowitz RJ (1992) Role of βγ subunits of G proteins in targeting the β-adrenergic receptor kinase to membrane-bound receptors. Science 257:1264–1267

    CAS  PubMed  Google Scholar 

  93. Purcell NH, Darwis D, Bueno OF, Müller JM, Schüle R, Molkentin JD (2004) Extracellular signal-regulated kinase 2 interacts with and is negatively regulated by the LIM-only protein FHL2 in cardiomyocytes. Mol Cell Biol 24:1081–1095

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Purcell NH, Wilkins BJ, York A, Saba-El-Leil MK, Meloche S, Robbins J, Molkentin JD (2007) Genetic inhibition of cardiac ERK1/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo. Proc Natl Acad Sci U S A 104:14074–14079

    CAS  PubMed Central  PubMed  Google Scholar 

  95. Purohit A, Rokita AG, Guan X, Chen B, Koval OM, Voigt N, Neef S, Sowa T, Gao Z, Luczak ED, Stefansdottir H, Behunin AC, Li N, El-Accaoui RN, Yang B, Swaminathan PD, Weiss RM, Wehrens XH, Song LS, Dobrev D, Maier LS, Anderson ME (2013) Oxidized Ca2+/calmodulin-dependent protein kinase II triggers atrial fibrillation. Circulation 128:1748–1757

    CAS  PubMed  Google Scholar 

  96. Raake PW, Vinge LE, Gao E, Boucher M, Rengo G, Chen X, DeGeorge BR Jr, Matkovich S, Houser SR, Most P, Eckhart AD, Dorn GW 2nd, Koch WJ (2008) G protein-coupled receptor kinase 2 ablation in cardiac myocytes before or after myocardial infarction prevents heart failure. Circ Res 103:413–422

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Ron D, Chen CH, Caldwell J, Jamieson L, Orr E, Mochly-Rosen D (1994) Cloning of an intracellular receptor for protein kinase C: a homolog of the β subunit of G proteins. Proc Natl Acad Sci U S A 91:839–843

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Rosenmund C, Carr DW, Bergeson SE, Nilaver G, Scott JD, Westbrook GL (1994) Anchoring of protein kinase A is required for modulation of AMPA/kainate receptors on hippocampal neurons. Nature 368:853–856

    CAS  PubMed  Google Scholar 

  99. Ruppert C, Deiss K, Herrmann S, Vidal M, Oezkur M, Gorski A, Weidemann F, Lohse MJ, Lorenz K (2013) Interference with ERKThr188 phosphorylation impairs pathological but not physiological cardiac hypertrophy. Proc Natl Acad Sci U S A 110:7440–7445

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Sbroggio M, Carnevale D, Bertero A, Cifelli G, De Blasio E, Mascio G, Hirsch E, Bahou WF, Turco E, Silengo L, Brancaccio M, Lembo G, Tarone G (2011) IQGAP1 regulates ERK1/2 and AKT signalling in the heart and sustains functional remodelling upon pressure overload. Cardiovasc Res 91:456–464

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Sheikh F, Raskin A, Chu PH, Lange S, Domenighetti AA, Zheng M, Liang X, Zhang T, Yajima T, Gu Y, Dalton ND, Mahata SK, Dorn GW 2nd, Brown JH, Peterson KL, Omens JH, McCulloch AD, Chen J (2008) An FHL1-containing complex within the cardiomyocyte sarcomere mediates hypertrophic biomechanical stress responses in mice. J Clin Invest 118:3870–3880

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Simonis G, Briem SK, Schoen SP, Bock M, Marquetant R, Strasser RH (2007) Protein kinase C in the human heart: differential regulation of the isoforms in aortic stenosis or dilated cardiomyopathy. Mol Cell Biochem 305:103–111

    CAS  PubMed  Google Scholar 

  103. Souroujon MC, Mochly-Rosen D (1998) Peptide modulators of protein-protein interactions in intracellular signaling. Nat Biotechnol 16:919–924

    CAS  PubMed  Google Scholar 

  104. Stathopoulou K, Cuello F, Candasamy AJ, Kemp EM, Ehler E, Haworth RS, Avkiran M (2014) Four-and-a-half LIM domains proteins are novel regulators of the protein kinase D pathway in cardiac myocytes. Biochem J 457:451–461

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Stebbins EG, Mochly-Rosen D (2001) Binding specificity for RACK1 resides in the V5 region of βII protein kinase C. J Biol Chem 276:29644–29650

    CAS  PubMed  Google Scholar 

  106. Stephens L, Smrcka A, Cooke FT, Jackson TR, Sternweis PC, Hawkins PT (1994) A novel phosphoinositide 3 kinase activity in myeloid-derived cells is activated by G protein βγ subunits. Cell 77:83–93

    CAS  PubMed  Google Scholar 

  107. Sternweis PC, Smrcka AV (1992) Regulation of phospholipase C by G proteins. Trends Biochem Sci 17:502–506

    CAS  PubMed  Google Scholar 

  108. 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

    CAS  PubMed  Google Scholar 

  109. Takeishi Y, Huang Q, Abe J, Che W, Lee JD, Kawakatsu H, Hoit BD, Berk BC, Walsh RA (2002) Activation of mitogen-activated protein kinases and p90 ribosomal S6 kinase in failing human hearts with dilated cardiomyopathy. Cardiovasc Res 53:131–137

    CAS  PubMed  Google Scholar 

  110. Tang WJ, Gilman AG (1991) Type-specific regulation of adenylyl cyclase by G protein βγ subunits. Science 254:1500–1503

    CAS  PubMed  Google Scholar 

  111. Thal DM, Homan KT, Chen J, Wu EK, Hinkle PM, Huang ZM, Chuprun JK, Song J, Gao E, Cheung JY, Sklar LA, Koch WJ, Tesmer JJ (2012) Paroxetine is a direct inhibitor of G protein-coupled receptor kinase 2 and increases myocardial contractility. ACS Chem Biol 7:1830–1839

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Tingley WG, Pawlikowska L, Zaroff JG, Kim T, Nguyen T, Young SG, Vranizan K, Kwok PY, Whooley MA, Conklin BR (2007) Gene-trapped mouse embryonic stem cell-derived cardiac myocytes and human genetics implicate AKAP10 in heart rhythm regulation. Proc Natl Acad Sci U S A 104:8461–8466

    CAS  PubMed Central  PubMed  Google Scholar 

  113. Ungerer M, Böhm M, Elce JS, Erdmann E, Lohse MJ (1993) Altered expression of beta-adrenergic receptor kinase and beta 1-adrenergic receptors in the failing human heart. Circulation 87:454–463

    CAS  PubMed  Google Scholar 

  114. Ungerer M, Kessebohm K, Kronsbein K, Lohse MJ, Richardt G (1996) Activation of β-adrenergic receptor kinase during myocardial ischemia. Circ Res 79:455–460

    CAS  PubMed  Google Scholar 

  115. van Berlo JH, Elrod JW, Aronow BJ, Pu WT, Molkentin JD (2011) Serine 105 phosphorylation of transcription factor GATA4 is necessary for stress-induced cardiac hypertrophy in vivo. Proc Natl Acad Sci U S A 108:12331–12336

    PubMed Central  PubMed  Google Scholar 

  116. Vidal M, Wieland T, Lohse MJ, Lorenz K (2012) β-Adrenergic receptor stimulation causes cardiac hypertrophy via a Gβγ/Erk-dependent pathway. Cardiovasc Res 96:255–264

    CAS  PubMed  Google Scholar 

  117. Völkers M, Weidenhammer C, Herzog N, Qiu G, Spaich K, von Wegner F, Peppel K, Müller OJ, Schinkel S, Rabinowitz JE, Hippe HJ, Brinks H, Katus HA, Koch WJ, Eckhart AD, Friedrich O, Most P (2011) The inotropic peptide βARKct improves βAR responsiveness in normal and failing cardiomyocytes through Gβγ-mediated L-type calcium current disinhibition. Circ Res 108:27–39

    PubMed Central  PubMed  Google Scholar 

  118. Wakasaki H, Koya D, Schoen FJ, Jirousek MR, Ways DK, Hoit BD, Walsh RA, King GL (1997) Targeted overexpression of protein kinase C β2 isoform in myocardium causes cardiomyopathy. Proc Natl Acad Sci U S A 94:9320–9325

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Wang S, Watanabe T, Noritake J, Fukata M, Yoshimura T, Itoh N, Harada T, Nakagawa M, Matsuura Y, Arimura N, Kaibuchi K (2007) IQGAP3, a novel effector of Rac1 and Cdc42, regulates neurite outgrowth. J Cell Sci 120:567–577

    CAS  PubMed  Google Scholar 

  120. White CD, Erdemir HH, Sacks DB (2012) IQGAP1 and its binding proteins control diverse biological functions. Cell Signal 24:826–834

    CAS  PubMed Central  PubMed  Google Scholar 

  121. Wittköpper K, Dobrev D, Eschenhagen T, El-Armouche A (2011) Phosphatase-1 inhibitor-1 in physiological and pathological beta-adrenoceptor signalling. Cardiovasc Res 91:392–401

    PubMed  Google Scholar 

  122. Wittköpper K, Fabritz L, Neef S, Ort KR, Grefe C, Unsold B, Kirchhof P, Maier LS, Hasenfuss G, Dobrev D, Eschenhagen T, El-Armouche A (2010) Constitutively active phosphatase inhibitor-1 improves cardiac contractility in young mice but is deleterious after catecholaminergic stress and with aging. J Clin Invest 120:617–626

    PubMed Central  PubMed  Google Scholar 

  123. Wu N, Hanson SM, Francis DJ, Vishnivetskiy SA, Thibonnier M, Klug CS, Shoham M, Gurevich VV (2006) Arrestin binding to calmodulin: a direct interaction between two ubiquitous signaling proteins. J Mol Biol 364:955–963

    CAS  PubMed Central  PubMed  Google Scholar 

  124. Xiao K, McClatchy DB, Shukla AK, Zhao Y, Chen M, Shenoy SK, Yates JR 3rd, Lefkowitz RJ (2007) Functional specialization of β-arrestin interactions revealed by proteomic analysis. Proc Natl Acad Sci U S A 104:12011–12016

    CAS  PubMed Central  PubMed  Google Scholar 

  125. Zhang R, Khoo MS, Wu Y, Yang Y, Grueter CE, Ni G, Price EE Jr, Thiel W, Guatimosim S, Song LS, Madu EC, Shah AN, Vishnivetskaya TA, Atkinson JB, Gurevich VV, Salama G, Lederer WJ, Colbran RJ, Anderson ME (2005) Calmodulin kinase II inhibition protects against structural heart disease. Nat Med 11:409–417

    CAS  PubMed  Google Scholar 

  126. Zhang T, Maier LS, Dalton ND, Miyamoto S, Ross J Jr, Bers DM, Brown JH (2003) The δC isoform of CaMKII is activated in cardiac hypertrophy and induces dilated cardiomyopathy and heart failure. Circ Res 92:912–919

    CAS  PubMed  Google Scholar 

Download references

Sources of funding

FC is supported by the DZHK (German Center for Cardiovascular Research) and the German Ministry of Research and Education (BMBF). KL is supported by the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich SFB688, TPA17) (to K.L.) and by the Bundesministerium für Bildung und Forschung (Comprehensive Heart Failure Center Würzburg; Project A2) (to K.L. and M.J.L.).

Disclosures

None.

Author information

Authors and Affiliations

  1. Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, 97078, Würzburg, Germany

    Kristina Lorenz & Evelyn Schmid

  2. Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany

    Kristina Lorenz & Petra Eder

  3. Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany

    Konstantina Stathopoulou & Friederike Cuello

  4. DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Lübeck, Germany

    Konstantina Stathopoulou & Friederike Cuello

  5. Department of Internal Medicine I—Cardiology, University Hospital Würzburg, Würzburg, Germany

    Petra Eder

Authors
  1. Kristina Lorenz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Konstantina Stathopoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Evelyn Schmid
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Petra Eder
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Friederike Cuello
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Kristina Lorenz or Friederike Cuello.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lorenz, K., Stathopoulou, K., Schmid, E. et al. Heart failure-specific changes in protein kinase signalling. Pflugers Arch - Eur J Physiol 466, 1151–1162 (2014). https://doi.org/10.1007/s00424-014-1462-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-014-1462-x

Keywords

Search

Navigation