Evidence for protein phosphatase inhibitor‐1 playing an amplifier role in β‐adrenergic signaling in cardiac myocytes

  title={Evidence for protein phosphatase inhibitor‐1 playing an amplifier role in $\beta$‐adrenergic signaling in cardiac myocytes},
  author={Ali El-Armouche and Thomas Rau and Oliver Zolk and Diana Ditz and Torsten Pamminger and Wolfram-Hubertus Zimmermann and Elmar J{\"a}ckel and Sian E. Harding and Peter Bokník and Joachim Neumann and Thomas Eschenhagen},
  journal={The FASEB Journal},
The protein phosphatase inhibitor‐1 (PPI‐1) inhibits phosphatase type‐1 (PP1) only when phosphorylated by protein kinase A and could play a pivotal role in the phosphorylation/dephosphorylation balance. Rat cardiac PPI‐1 was cloned by reverse transcriptase‐polymerase chain reaction, expressed in Eschericia coli, evaluated in phosphatase assays, and used to generate an antiserum. An adenovirus was constructed encoding PPI‐1 and green fluorescent protein (GFP) under separate cytomegalovirus… 
Phospholemman‐dependent regulation of the cardiac Na/K‐ATPase activity is modulated by inhibitor‐1 sensitive type‐1 phosphatase
This work provides the first physiological and biochemical evidence that PLM phosphorylation and cardiac Na/K‐ATPase activity are negatively regulated by PP‐1 and that this regulatory mechanism could be counteracted by I‐1.
Inhibition of protein phosphatase 1 by inhibitor‐2 gene delivery ameliorates heart failure progression in genetic cardiomyopathy
  • M. Yamada, Y. Ikeda, M. Matsuzaki
  • Biology, Chemistry
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology
  • 2006
Results indicate that increased PP1 activity is an exacerbating factor during progression of genetic cardiomyopathy and modulation ofPP1 activity by INH‐2 provides a potential new treatment for HF without activating protein kinase A signaling in cardiomeocytes.
AAV-9 mediated phosphatase-1 inhibitor-1 overexpression improves cardiac contractility in unchallenged mice but is deleterious in pressure-overload
The data suggest that AAV9-mediated cardiac-specific overexpression of I-1c, previously associated with enhanced calcium cycling, improves cardiac contractile function in unchallenged animals but failed to protect against cardiac remodeling induced by hemodynamic stress questioning the use of I -1c as a potential strategy to treat heart failure in conditions with increased afterload.
Role of protein phosphatase-1 inhibitor-1 in cardiac physiology and pathophysiology.
Activation of endogenous protein phosphatase 1 enhances the calcium sensitivity of the ryanodine receptor type 2 in murine ventricular cardiomyocytes
The approach unmasks the functional importance of PP‐1 in the regulation of RyR2 activity, suggesting a potential role in the generation of a pathophysiological sarcoplasmic reticulum Ca2+ leak in the diseased heart.
Identification of a Novel Phosphorylation Site in Protein Phosphatase Inhibitor-1 as a Negative Regulator of Cardiac Function*
Phosphorylation of inhibitor-1 at threonine 75 represents a new mechanism of cardiac contractility regulation, partially through the alteration of sarcoplasmic reticulum calcium transport activity.
Constitutively active phosphatase inhibitor-1 improves cardiac contractility in young mice but is deleterious after catecholaminergic stress and with aging.
Conditional expression of I-1c or I- 1S67A enhanced steady-state phosphorylation of 2 key Ca2+-regulating sarcoplasmic reticulum enzymes, associated with increased contractile function in young animals but also with arrhythmias and cardiomyopathy after adrenergic stress and with aging.


Is myosin phosphatase regulated in vivo by inhibitor‐1? Evidence from inhibitor‐1 knockout mice
I‐1 may play a role as a fine‐tuning mechanism involved in regulating portal vein responsiveness to β‐adrenergic agonists, and its activation by PKA in the aorta does not appear to play a significant role in contractile or relaxant responses to any pharmacomechanical or electromechanical agonists used.
Evidence for presence and hormonal regulation of protein phosphatase inhibitor-1 in ventricular cardiomyocyte.
A decrease in type 1 protein phosphatase activity through phosphorylation of PPI-1 may be an important pathway for augmenting cardiac contractility.
Type 1 Phosphatase, a Negative Regulator of Cardiac Function
PP1 is an important regulator of cardiac function, and inhibition of its activity may represent a novel therapeutic target in heart failure.
Multiple structural elements define the specificity of recombinant human inhibitor-1 as a protein phosphatase-1 inhibitor.
The data point to multiple interactions between the I-1 functional domain.
Phosphorylation of DARPP-32 and protein phosphatase inhibitor-1 in rat choroid plexus: regulation by factors other than dopamine
The results indicate that DARPP-32, known to be regulated by dopamine in a number of tissues, can be phosphorylated in response to non-dopaminergic factors, including hormones acting through non-cAMP-dependent pathways.
Autonomic regulation of type 1 protein phosphatase in cardiac muscle.
It is concluded that inhibitor-1 and type 1 phosphatase can be regulated in intact cardiac muscle by agents that increase intracellular cAMP and by acetylcholine.
Evidence for isoproterenol-induced phosphorylation of phosphatase inhibitor-1 in the intact heart.
It is concluded that a protein, probably identical to phosphatase inhibitor-1, is phosphorylated in vivo in the heart in the presence of isoproterenol.
Molecular cloning of protein phosphatase inhibitor-1 and its expression in rat and rabbit tissues.
Physiologic importance of protein phosphatase inhibitors.
This review examines the role played by endogenous inhibitors of three major protein serine/threonine phosphatases, PP1, PP2A and PP2B in the control of cell physiology and establishes phosphatase regulation as a key feature of hormone signaling.
Protein Phosphatase-1 Regulation in the Induction of Long-Term Potentiation: Heterogeneous Molecular Mechanisms
Examination of the performance of I-1 mutants in spatial learning tests indicated that intact LTP at lateral perforant path–granule cell synapses is either redundant or is not involved in this form of learning, suggesting protein phosphatase-1-mediated regulation of NMDA receptor-dependent synaptic plasticity involves heterogeneous molecular mechanisms.