Raf kinase inhibitor protein: lessons of a better way for β‐adrenergic receptor activation in the heart

Stimulation of β‐adrenergic receptors (βARs) provides the most efficient physiological mechanism to enhance contraction and relaxation of the heart. Activation of βARs allows rapid enhancement of myocardial function in order to fuel the muscles for running and fighting in a fight‐or‐flight response. Likewise, βARs become activated during cardiovascular disease in an attempt to counteract the restrictions of cardiac output. However, long‐term stimulation of βARs increases the likelihood of cardiac arrhythmias, adverse ventricular remodelling, decline of cardiac performance and premature death, thereby limiting the use of βAR agonists in the treatment of heart failure. Recently the endogenous Raf kinase inhibitor protein (RKIP) was found to activate βAR signalling of the heart without adverse effects. This review will summarize the current knowledge on RKIP‐driven compared to receptor‐mediated signalling in cardiomyocytes. Emphasis is given to the differential effects of RKIP on β1‐ and β2‐ARs and their downstream targets, the regulation of myocyte calcium cycling and myofilament activity.

• Publication year

  2017

• Venue

  Journal of Physiology

• Publication date

  2017-04-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1113/JP274064PMID 28444807PMCID 5471367
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure

  2016cited by this paper
• A Raf kinase inhibitor demonstrates antiviral activities both in vitro and in vivo against different genotypes of virulent Newcastle disease virus.

  2016cited by this paper
• Chronic heart failure: Ca(2+), catabolism, and catastrophic cell death.

  2016cited by this paper
• Pharmacology of heart failure: From basic science to novel therapies.

  2016cited by this paper
• CaMKII-dependent phosphorylation of RyR2 promotes targetable pathological RyR2 conformational shift.

  2016cited by this paper
• 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure

  2016influential reference
• Analyzing ERK 1/2 signalling and targets.

  2016cited by this paper
• Intracoronary Gene Transfer of Adenylyl Cyclase 6 in Patients With Heart Failure: A Randomized Clinical Trial.

  2016cited by this paper
• β‐adrenergic receptor signalling and its functional consequences in the diseased heart

  2016cited by this paper
• Calcium Ions in Inherited Cardiomyopathies.

  2016cited by this paper
• Role of protein phosphatase inhibitor-1 in cardiac beta adrenergic pathway.

  2016cited by this paper
• S100A1 DNA-based Inotropic Therapy Protects Against Proarrhythmogenic Ryanodine Receptor 2 Dysfunction.

  2015cited by this paper
• Troponin I Mutations R146G and R21C Alter Cardiac Troponin Function, Contractile Properties, and Modulation by Protein Kinase A (PKA)-mediated Phosphorylation*

  2015cited by this paper
• Cardiac RKIP induces a beneficial β-adrenoceptor–dependent positive inotropy

  2015influential reference
• Gene therapy for heart failure.

  2015cited by this paper
• Targets for therapy in sarcomeric cardiomyopathies.

  2015cited by this paper
• Prevalence of AAV1 neutralizing antibodies and consequences for a clinical trial of gene transfer for advanced heart failure

  2015cited by this paper
• Seven-transmembrane receptors

  2015cited by this paper
• Heart failure-specific changes in protein kinase signalling

  2014influential reference
• Adrenergic signaling in heart failure: a balance of toxic and protective effects

  2014cited by this paper
• Enhanced Expression of &bgr;3-Adrenoceptors in Cardiac Myocytes Attenuates Neurohormone-Induced Hypertrophic Remodeling Through Nitric Oxide Synthase

  2014cited by this paper
• Design of a phase 2b trial of intracoronary administration of AAV1/SERCA2a in patients with advanced heart failure: the CUPID 2 trial (calcium up-regulation by percutaneous administration of gene therapy in cardiac disease phase 2b).

  2014cited by this paper
• Phospholamban interactome in cardiac contractility and survival: A new vision of an old friend.

  2014cited by this paper
• RKIP: a governor of intracellular signaling.

  2014influential reference
• Cardiac sarcoplasmic reticulum calcium leak: basis and roles in cardiac dysfunction.

  2014influential reference
• Desensitization of Myofilaments to Ca2+ as a Therapeutic Target for Hypertrophic Cardiomyopathy With Mutations in Thin Filament Proteins

  2014cited by this paper
• Cardiac calcium handling on trial: targeting the failing cardiomyocyte signalosome.

  2014influential reference
• Cardiac AAV 9S 100 A 1 gene therapy rescues postischemic heart failure in a preclinical large animal model

  2014cited by this paper
• Interference with ERKThr188 phosphorylation impairs pathological but not physiological cardiac hypertrophy

  2013cited by this paper
• Spatial control of the βAR system in heart failure: the transverse tubule and beyond.

  2013cited by this paper
• Cardiotoxic and Cardioprotective Features of Chronic &bgr;-Adrenergic Signaling

  2013cited by this paper
• Inhibition of G-protein-coupled Receptor Kinase 2 (GRK2) Triggers the Growth-promoting Mitogen-activated Protein Kinase (MAPK) Pathway*

  2013cited by this paper
• Beta3-adrenoreceptors in cardiovasular diseases: new roles for an "old" receptor.

  2013cited by this paper
• Calcium cycling proteins and heart failure: mechanisms and therapeutics.

  2013cited by this paper
• Deletion of the β2-adrenergic receptor prevents the development of cardiomyopathy in mice.

  2013influential reference
• Epac2 Mediates Cardiac &bgr;1-Adrenergic–Dependent Sarcoplasmic Reticulum Ca2+ Leak and Arrhythmia

  2013cited by this paper
• Beyond the cardiac myofilament: hypertrophic cardiomyopathy- associated mutations in genes that encode calcium-handling proteins.

  2012cited by this paper
• Molecular targets in heart failure gene therapy: current controversies and translational perspectives

  2012influential reference
• β-Adrenergic receptor subtype signaling in heart: From bench to bedside

  2012cited by this paper
• β-Adrenergic receptor stimulation causes cardiac hypertrophy via a Gβγ/Erk-dependent pathway.

  2012cited by this paper
• High Levels of Circulating Epinephrine Trigger Apical Cardiodepression in a &bgr;2-Adrenergic Receptor/Gi–Dependent Manner: A New Model of Takotsubo Cardiomyopathy

  2012cited by this paper
• Dobutamine for patients with severe heart failure: a systematic review and meta-analysis of randomised controlled trials

  2012influential reference
• Raf Kinase Inhibitor Protein (RKIP) Dimer Formation Controls Its Target Switch from Raf1 to G Protein-coupled Receptor Kinase (GRK) 2*

  2012cited by this paper
• Prospects for gene transfer for clinical heart failure

  2012cited by this paper
• Role of RyR2 Phosphorylation at S2814 During Heart Failure Progression

  2012cited by this paper
• Myocardial infarction in mice alters sarcomeric function via post-translational protein modification

  2011cited by this paper
• A Critical Function for Ser-282 in Cardiac Myosin Binding Protein-C Phosphorylation and Cardiac Function

  2011cited by this paper
• A Novel Preclinical Strategy for Identifying Cardiotoxic Kinase Inhibitors and Mechanisms of Cardiotoxicity

  2011cited by this paper
• The Inotropic Peptide &bgr;ARKct Improves &bgr;AR Responsiveness in Normal and Failing Cardiomyocytes Through G&bgr;&ggr;-Mediated L-Type Calcium Current Disinhibition

  2011influential reference
• Inherited dysfunction of sarcoplasmic reticulum Ca2+ handling and arrhythmogenesis.

  2011cited by this paper
• Serine 105 phosphorylation of transcription factor GATA4 is necessary for stress-induced cardiac hypertrophy in vivo

  2011cited by this paper
• Cardiac AAV9-S100A1 Gene Therapy Rescues Post-Ischemic Heart Failure in a Preclinical Large Animal Model

  2011cited by this paper
• β₂ AR agonists in treatment of chronic heart failure: long path to translation.

  2011cited by this paper
• Ca2+ cycling and new therapeutic approaches for heart failure.

  2010cited by this paper
• β2-Adrenergic Receptor Redistribution in Heart Failure Changes cAMP Compartmentation

  2010influential reference
• Role of the cAMP-binding protein Epac in cardiovascular physiology and pathophysiology

  2010cited by this paper
• Increased myofilament Ca2+-sensitivity and arrhythmia susceptibility.

  2010cited by this paper
• Is ryanodine receptor phosphorylation key to the fight or flight response and heart failure?

  2010cited by this paper
• Abnormalities of calcium metabolism and myocardial contractility depression in the failing heart

  2009influential reference
• Alterations of Phospholamban Function Can Exhibit Cardiotoxic Effects Independent of Excessive Sarcoplasmic Reticulum Ca2+-ATPase Inhibition

  2009cited by this paper
• Cardiac hypertrophy: targeting Raf/MEK/ERK1/2-signaling.

  2009cited by this paper
• &agr;1-Adrenergic Receptor Subtypes in Nonfailing and Failing Human Myocardium

  2009cited by this paper
• ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: application of natriuretic peptides.

  2008influential reference
• Raf Kinase Inhibitory Protein Function Is Regulated via a Flexible Pocket and Novel Phosphorylation-Dependent Mechanism

  2008cited by this paper
• Gene therapy in heart failure.

  2008cited by this paper
• Effects of clenbuterol on contractility and Ca2+ homeostasis of isolated rat ventricular myocytes.

  2008cited by this paper
• Epac Mediates &bgr;-Adrenergic Receptor–Induced Cardiomyocyte Hypertrophy

  2008cited by this paper
• Raf kinase inhibitory protein: a signal transduction modulator and metastasis suppressor

  2008cited by this paper
• Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice.

  2008cited by this paper
• Phosphatase inhibitor-1-deficient mice are protected from catecholamine-induced arrhythmias and myocardial hypertrophy.

  2008influential reference
• Cardioprotective and Survival Benefits of Long-Term Combined Therapy with β2 Adrenoreceptor (AR) Agonist and β1 AR Blocker in Dilated Cardiomyopathy Postmyocardial Infarction

  2008cited by this paper
• An FHL1-containing complex within the cardiomyocyte sarcomere mediates hypertrophic biomechanical stress responses in mice.

  2008cited by this paper
• t-Tubules and sarcoplasmic reticulum function in cardiac ventricular myocytes.

  2007cited by this paper
• Genetic inhibition of cardiac ERK1/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo

  2007cited by this paper
• Role of Ca2+/calmodulin-dependent protein kinase (CaMK) in excitation-contraction coupling in the heart.

  2007cited by this paper
• Effect of levosimendan on ventricular arrhythmias and prognostic autonomic indexes in patients with decompensated advanced heart failure secondary to ischemic or dilated cardiomyopathy.

  2006cited by this paper
• Protein kinase-A phosphorylates titin in human heart muscle and reduces myofibrillar passive tension

  2006cited by this paper
• Regulation of cardiac hypertrophy by intracellular signalling pathways

  2006cited by this paper
• Modulation of the MAP kinase signaling cascade by Raf kinase inhibitory protein

  2005cited by this paper
• Beta-arrestin-recruited phosphodiesterase-4 desensitizes the AKAP79/PKA-mediated switching of beta2-adrenoceptor signalling to activation of ERK.

  2005cited by this paper
• β-Arrestin-recruited phosphodiesterase-4 desensitizes the AKAP79/PKA-mediated switching of β2-adrenoceptor signalling to activation of ERK

  2005cited by this paper
• Regional distribution of β1- and β2-adrenoceptors in the failing and nonfailing human heart

  2004cited by this paper
• Raf-1 Kinase Is Required for Cardiac Hypertrophy and Cardiomyocyte Survival in Response to Pressure Overload

  2004cited by this paper
• Alterations in Myofilament Function Contribute to Left Ventricular Dysfunction in Pigs Early After Myocardial Infarction

  2004cited by this paper
• Protecting the myocardium: A role for the &bgr;2 adrenergic receptor in the heart

  2004cited by this paper
• Activation of Raf-1 Signaling by Protein Kinase C through a Mechanism Involving Raf Kinase Inhibitory Protein*

  2003cited by this paper
• Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human.

  2003cited by this paper
• Dilated Cardiomyopathy and Heart Failure Caused by a Mutation in Phospholamban

  2003cited by this paper
• Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2

  2003influential reference
• Signalling: Seven-transmembrane receptors

  2002cited by this paper
• Seven-transmembrane-spanning receptors and heart function

  2002influential reference
• Subtype specific roles of beta-adrenergic receptors in apoptosis of adult rat ventricular myocytes.

  2002cited by this paper
• Controlled expression of cardiac-directed adenylylcyclase type VI provides increased contractile function.

  2002cited by this paper
• Dancing with different partners: protein kinase a phosphorylation of seven membrane-spanning receptors regulates their G protein-coupling specificity.

  2002cited by this paper
• Calcium cycling in congestive heart failure.

  2002cited by this paper
• The Phosphatidylethanolamine-binding Protein Is the Prototype of a Novel Family of Serine Protease Inhibitors*

  2001cited by this paper
• The enhanced contractility of the phospholamban-deficient mouse heart persists with aging.

  2001cited by this paper
• Inotropic therapy for heart failure: an evidence-based approach.

  2001influential reference
• Raf Kinase Inhibitor Protein Interacts with NF-κB-Inducing Kinase and TAK1 and Inhibits NF-κB Activation

  2001cited by this paper
• Raf kinase inhibitor protein interacts with NF-kappaB-inducing kinase and TAK1 and inhibits NF-kappaB activation.

  2001cited by this paper

• Protein Kinase A Phosphorylates a Conformationally High-Energy State of Raf Kinase Inhibitory Protein.

  2025cites this paper
• Molecular insights driving personalized therapies.

  2025cites this paper
• PKA restricts ERK signaling in learning and memory Kenyon cell neurons.

  2025cites this paper
• RASopathies and Cardiac Complications: Insights into Mechanisms, Diagnosis, and Innovative Treatments.

  2025cites this paper
• Remodeling of T-Tubules and Associated Calcium Handling Dysfunction in Heart Failure: Mechanisms and Therapeutic Insights.

  2024cites this paper
• From "contraindicated" to "first line" - Current mechanistic insights beyond canonical β-receptor signaling.

  2024cites this paper
• From Ca2+ dysregulation to heart failure: β-adrenoceptor activation by RKIP postpones molecular damages and subsequent cardiac dysfunction in mice carrying mutant PLNR9C by correction of aberrant Ca2+-handling.

  2024cites this paper
• Trametinib alters contractility of paediatric Noonan syndrome‐associated hypertrophic myocardial tissue slices

  2024cites this paper
• Salbutamol attenuates arrhythmogenic effect of aminophylline in a hPSC-derived cardiac model

  2024cites this paper
• RKIP localizes to the nucleus through a bipartite nuclear localization signal and interaction with importin α to regulate mitotic progression.

  2023cites this paper
• Harnessing RKIP to Combat Heart Disease and Cancer

  2022cites this paper
• Rubicon-regulated beta-1 adrenergic receptor recycling protects the heart from pressure overload

  2022cites this paper
• Raf Kinase Inhibitory Protein regulates the cAMP-dependent protein kinase signaling pathway through a positive feedback loop

  2022cites this paper
• Insights of RKIP-Derived Suppression of Prostate Cancer

  2021cites this paper
• The alpha2 isoform of the Na+/K+-ATPase protects against pathological remodeling and β-adrenergic desensitization after myocardial infarction.

  2021cites this paper
• Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies

  2021cites this paper
• RKIP in human diseases and its potential as a prognostic indicator and therapeutic target

  2020cites this paper
• Dose-Dependent Effects of Long-Term Administration of Hydrogen Sulfide on Myocardial Ischemia–Reperfusion Injury in Male Wistar Rats: Modulation of RKIP, NF-κB, and Oxidative Stress

  2020cites this paper
• Impact of Kidney Function on the Blood Proteome and on Protein Cardiovascular Risk Biomarkers in Patients With Stable Coronary Heart Disease

  2020cites this paper
• Alterations in the Sympathetic and Parasympathetic Nervous Systems in Heart Failure

  2020cites this paper
• The N-termini of GRK2 and GRK3 simulate the stimulating effects of RKIP on β-adrenoceptors.

  2019cites this paper
• Conserved salt-bridge competition triggered by phosphorylation regulates the protein interactome

  2017cites this paper
• Cardiac regulatory mechanisms: new concepts and challenges

  2017cites this paper
• Calcium Ions in Inherited Cardiomyopathies.

  2016cites this paper