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Calcium transient in cardiomyocytes is regulated by multiple protein kinases and phosphatases. Cyclic and effective cardiac contraction and relaxation depend on the appropriately timed generation and spread of cardiac electrical activity.
At the cellular level, excitation-contraction E-C coupling is initiated by action potential depolarization resulting, via a cascade of events, in an increase in intracellular calcium concentration, which ultimately leads to activation of myofilament and muscle contraction; subsequent removal of intracellular calcium via a number of mechanisms results in detachment of myosin cross-bridges and relaxation.
Excitation and contraction involve multiple trans-membrane e. Studies of reversible protein phosphorylation in the heart date back to early seventies of last century when it was reported that cardiac troponin I cTnI was phosphorylated and dephosphorylated in the same manner as the protein substrates involved in glycogen metabolism England et al.
PP2A came into spotlight of heart research following another line of observation in late s and early s. It was found that an extract from black sea sponge, okadaic acid, has positive inotropic effect on electro-mechanic properties of ventricular muscle and enhances pacemaker activities in rabbit SA node preparation Kodama et al. Okadaic acid inhibits protein phosphatase PP2A at very low concentration leading to increased phosphorylation in numerous proteins of mammalian cells, including a number of ion channels and myofilament regulatory proteins.
Thus, PP2A coordinates cardiac excitation and contraction. For a long time, mammalian protein phosphatases had been considered constitutively active with the regulatory function fulfilled solely by protein kinases.
This notion has become obsolete with discovery of multiple regulatory mechanisms for protein phosphatases, especially those that link phosphatase activities to extracellular cues Cohen, The importance of regulation of phosphatases in heart pathophysiology becomes more obvious when altered PP2A expression and activities are closely associated with heart diseases Ai and Pogwizd, ; Ke et al.
PP2A actually refer to a large family of distinct heterotrimeric protein phosphatases that share a common core enzyme consisting of a scaffolding A and a catalytic C subunits that associate with a B subunit Figure 1.
HEAT repeat exists in proteins with different functions that form helical structures and provide structural flexibility to PP2A-A subunit Grinthal et al.
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Formation of the PP2A heterotrimer follows a sequential pattern in that the core enzyme AC arises first and then binds to the B subunit.
The Tyrosine and Leucine show reversible phosphorylation and methylation that determine the phosphatase localization and substrate specificity Chen et al. Methylation of Leucine diverts the C-terminal carboxyl group from a repulsive negative charge interaction and facilitates assembly of ABC holoenzyme Cho and Xu, PP2A heterotrimer and the subunits. The catalytic C subunit can be tyrosine phosphorylated at tyrosine and methylated at Leucine The regulatory subunits of PP2A have many members with large sequence diversity and are coded by at least 17 distinct genes.
It remains unclear if D containing these B subunits control cyclic dephophorylation on any protein substrates. A genome wide leii studies has identified a deletion mutation that links abnormal striatin mRNA accumulation to arrhythmogenic right ventricular cardiomyopathy in canine model Meurs et al. Their expression and functional role in cardiomyocytes is underexplored.
PP2A is also up-regulated by small molecular weight chemicals, both native and artificial. FTY fingolimod is a synthetic analog of C 2 and C 6 ceramide and an immunosuppressor used for treatment of multiple schlerosis Kappos et al. Accumulating evidence has indicated that PP2A activities are up-regulated by stimulation of the inhibitory G proteins, Gi through different intermediate signaling processes Ke et al.
In cardiomyocytes, methylation of PP2Ac is reduced when the cells are treated with pertussis toxin and the same result is generated by inhibition of p38 MAP kinase Liu and Hofmann, Cdc42 and Rac1 have been shown to be the downstream effectors for Gi in cardiomycytes and other mammalian cells.
The constitutively active Pak1, the downstream effectors for Cdc42 and Rac1 induces activation of PP2A and dephosphorylation of myofilament regulatory proteins Ke et al. A balance of protein kinase and phosphatase activities is required to maintain normal cardiac functions. Breakdown of the balance occurs at different levels: In pacemaker cells, activation of PP2A by its upstream signal, Pak1, represses isoproterenol stimulated enhancement of the channel activities Ke et al.
Ser and Ser are considered as the PKA sites. On the other hand, Yang et al. PP1 and PP2A form complexes on ryanodine receptors. PP1 is the major phosphatase that removes phosphate from both locations. The gap junction channel protein connexin 43 conducts ions and other small molecules between two adjacent myocytes. Therefore, abnormality in PP2A expression, localization and activities are frequently associated with heart failure.
However, the role of PP2A as a causal or beneficial factor in heart failure remains unclear. In a rat model with chronic isoproterenol infusion that lead to cardiac hypertrophy and heart failure, PP2A activities increased significantly at day 2 Boknik et al. Overexpression of the catalytic subunit of PP2A PP2A-C by transgenic approach in mouse heart leads to left ventricular hypertrophy and reduced contractility along with an increase of PP2A activities in myocardium Gergs et al.
A more detailed analysis of expression and localization of different PP2A B subunits in cardiomyocytes from normal and failing hearts indicate that proper targeting and localization of PP2A holoenzyme are important for normal cardiac functions DeGrande et al.
Further analysis indicates that reduction of L-type calcium current density is due to a transcriptional downregulation of the pore forming alpha 1c -subunit of LTCC, while single channel peak average current is 1. The A subunit is also phosphorylated and phosphorylation attenuates assembly of PP2A heterotrimer and reduces PP2A activities characterized by le phosphorylation occurred to a large number of proteins in cells expressing the peudophosphorylated constructs.
In transgenic mice expressing a truncated A subunit that is a dominant negative mutant disrupting normal PP2a assembly, dilated cardiomyopathy 16294 with increased end-diastolic and end-systolic dimensions and decreased fractional shortening Brewis et al.
Structural diversity and complex regulation of PP2A constitute a significant 20112 in understanding its function in the heart. Emerging evidence begins to point out connections between specific PP2A heterotrimers and their protein substrates in cardiomyocytes, but definitive results are still scarce.
Application of general PP2A inhibitors for heart diseases may not fe applicable as these inhibitors usually are tumorigenic. However, cardiac conditions including heart failure may become ameliorated by elevating PP2A activities. FTY protect heart against ischemia-reperfusion induced arrhythmia and has demonstrated anti-hypertrophic effect in mouse TAC model Liu et al. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
John Solaro, Yunbo Ke. Enhanced activation of pactivated kinase 1 in heart failure contributes to dephosphorylation of connexin Connexin 43 downregulation and dephosphorylation in nonischemic heart failure is associated with enhanced colocalized protein phosphatase type 2A.
MicroRNA-1 and increase arrhythmogenesis in heart failure by dissociating phosphatase activity from RyR2 complex. Facilitation of murine cardiac L-type Ca v 1. Protein phosphatase activity is increased in a rat model of long-term beta-adrenergic stimulation.
Dilated cardiomyopathy in transgenic mice expressing a mutant A subunit of protein phosphatase 2A. Impaired beta-adrenergic responsiveness accentuates dysfunctional excitation-contraction coupling ed an ovine model of tachypacing-induced heart failure.
Striatins contain a noncanonical coiled coil that binds protein phosphatase 2A A subunit to form a 2: Lwi of protein serine-threonine phosphatase type-2A by tyrosine phosphorylation. Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme.
Functional interplay between dual site phospholambam phosphorylation: Mutation of Tyr and Leu in the protein phosphatase 2A catalytic subunit favors association with the alpha 4 subunit which promotes dephosphorylation of 126994 factor Protein phosphorylation and hormone action. The phosphorylation of troponin I from cardiac muscle. Protein phosphatase 2A is associated with class C L-type calcium channels Cav1.
Molecular mechanisms underlying cardiac protein phosphatase 2A regulation in heart. The epsilon subtype of protein kinase C is required for cardiomyocyte llei phosphorylation. Ceramide activates heterotrimeric protein phosphatase 2A. Dephosphorylation of the inhibitor component of troponin by phosphorylase dw. Overexpression of the catalytic subunit of protein phosphatase 2A impairs cardiac function. M2-specific muscarinic cholinergic receptor-mediated inhibition of cardiac regulatory protein phosphorylation.
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A1-adenosine receptor-mediated inhibition of isoproterenol-stimulated protein phosphorylation in ventricular myocytes. Evidence against a cAMP-dependent effect. Binding of protein phosphatase 2A to the L-type calcium channel Cav1. Oral fingolimod FTY for relapsing multiple sclerosis.
Regulation of L-type calcium channel and delayed rectifier potassium channel activity by pactivated kinase-1 in guinea pig sinoatrial node pacemaker cells.
Regulation of cardiac excitation and contraction by p21 activated kinase Use of a decoy peptide to purify p21 activated kinase-1 in cardiac muscle and identification of ceramide-related activation. Intracellular localization and functional effects of Pactivated kinase-1 Pak1 in cardiac myocytes.
Phosphorylation of troponin I by protein kinase A accelerates relaxation and crossbridge cycle kinetics in mouse ventricular muscle. Increased open probability of single cardiac L-type calcium channels in patients with chronic atrial fibrillation. Electromechanical effects of okadaic acid isolated from black sponge in guinea-pig ventricular muscles.
Electrical effects of okadaic acid extracted from black sponge on rabbit sinus node. Purification and characterization of two potent heat-stable protein inhibitors of protein phosphatase 2A from bovine kidney.
Prevalence and genetic diversity analysis of human coronaviruses among cross-border children
A full range of mouse sinoatrial node AP firing rates requires protein kinase A-dependent calcium signaling. Antiadrenergic effects of adenosine A 1 receptor-mediated protein phosphatase 2a activation in the heart. Modulation of protein phosphatase 2a by adenosine A1 receptors in cardiomyocytes: Pak1 as a novel therapeutic target for antihypertrophic treatment in the heart. Regulation ds PP2AC carboxylmethylation and cellular localisation by inhibitory class G-protein coupled receptors in cardiomyocytes.
Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation. Regional expression of protein phosphatase type 1 and 2A catalytic subunit isoforms in the human heart.
Identification of the 112694 protein phosphatases in mammalian cardiac muscle which dephosphorylate phospholamban. Three-dimensional localization of serinea phosphorylation site in cardiac ryanodine receptor.
Structural basis for protein phosphatase 1 regulation and specificity. Phosphorylation of troponin I and the inotropic effect of adrenaline in the perfused rabbit heart. Phosphorylation of connexin at serine promotes a cardiac injury-resistant state.
Phosphorylation of the inhibitor component of troponin by phosphorylase kinase.