Cardiac Troponin I Phosphorylation Increases the Rate of Cardiac Muscle Relaxation

Zhang, Ren; Zhao, Jiaju; Mandveno, Alan; Potter, James D.

doi:10.1161/01.res.76.6.1028

Cited by 293 publications

(284 citation statements)

References 36 publications

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“…The simulations suggested a desensitization of the myofilament to calcium in Pkd2 +/− mice under baseline conditions, which is a known effect of TnI phosphorylation (28). Consistent with our model, we found that the phosphorylation status of TnI at the PKA phosphorylation site Ser22/23 in Pkd2 +/− mice was 90% higher than in WT mice (Fig.…”

Section: Resultssupporting

confidence: 88%

Decreased polycystin 2 expression alters calcium-contraction coupling and changes β-adrenergic signaling pathways

Kuo¹,

Kwaczala

Nguyen³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Cardiac disorders are the main cause of mortality in autosomaldominant polycystic kidney disease (ADPKD). However, how mutated polycystins predispose patients with ADPKD to cardiac pathologies before development of renal dysfunction is unknown. We investigate the effect of decreased levels of polycystin 2 (PC2), a calcium channel that interacts with the ryanodine receptor, on myocardial function. We hypothesize that heterozygous PC2 mice (Pkd2 +/− ) undergo cardiac remodeling as a result of changes in calcium handling, separate from renal complications. We found that Pkd2 +/− cardiomyocytes have altered calcium handling, independent of desensitized calcium-contraction coupling. Paradoxically, in Pkd2 +/− mice, protein kinase A (PKA) phosphorylation of phospholamban (PLB) was decreased, whereas PKA phosphorylation of troponin I was increased, explaining the decoupling between calcium signaling and contractility. In silico modeling supported this relationship. Echocardiography measurements showed that Pkd2 +/− mice have increased left ventricular ejection fraction after stimulation with isoproterenol (ISO), a β-adrenergic receptor (βAR) agonist. Blockers of βAR-1 and βAR-2 inhibited the ISO response in Pkd2 +/− mice, suggesting that the dephosphorylated state of PLB is primarily by βAR-2 signaling. Importantly, the Pkd2 +/− mice were normotensive and had no evidence of renal cysts. Our results showed that decreased PC2 levels shifted the βAR pathway balance and changed expression of calcium handling proteins, which resulted in altered cardiac contractility. We propose that PC2 levels in the heart may directly contribute to cardiac remodeling in patients with ADPKD in the absence of renal dysfunction.calcium signaling | β-adrenergic receptor blocker | excitation contraction coupling

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Section: Resultssupporting

confidence: 88%

Decreased polycystin 2 expression alters calcium-contraction coupling and changes β-adrenergic signaling pathways

Kuo¹,

Kwaczala

Nguyen³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…3A shows that after PKA treatment the Ca 2+ sensitivity of the fibres reconstituted with wild-type TnI was significantly reduced by 0.22 pCa units (from 5.35 + 0.015 to 5.13 + 0.04, n = 5). This change in Ca 2+ sensitvity induced by PKA was similar to that observed by others [9].…”

Section: ? Effect Of Extraction and Reconstitution Of Tni And Tncsupporting

confidence: 91%

“…In the heart, phosphorylation of TnI by PKA occurs following fladrenergic stimulation [17] and may be considered as an adaptive mechanism to prevent overstimulation. The phosphorylation of cardiac TnI has been shown to reduce the affinity of TnC for Ca 2+ [18], thus, promoting more rapid relaxation [9]. Different TnI isoforms from various tissues have been overexpressed in bacterial systems [19,20] and a number of mutants have been produced in order to investigate the structur~func-tion relationship in TnI [7,10,[21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Reconstitution of skinned cardiac fibres with human recombinant cardiac troponin‐I mutants and troponin‐C

et al. 1995

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“…The HCTnI mutants (R145G and A86T,R145G) were formed by overlapping PCR using HCTnI cDNA previously cloned in our laboratory from human cardiac tissue (23). The sequence of the TnI mutants was verified by sequencing prior to expression and purification.…”

Section: Mutation Expression and Purification Of Hctni And Hctni R1mentioning

confidence: 99%

“…Preparation of Porcine Skinned Cardiac Muscle Bundles-Cardiac skinned muscle fibers were prepared following a common laboratory procedure published by Zhang et al (23). Freshly isolated porcine hearts were incubated in an O 2 -saturated solution containing 140 mM NaCl, 4 mM KCl, 1.8 mM CaCl 2 , 1 mM MgCl 2 , 1.8 mM NaHPO 4 , 5.5 mM glucose, and 5 mM HEPES, pH 7.4.…”

Section: Mutation Expression and Purification Of Hctni And Hctni R1mentioning

confidence: 99%

Functional Analysis of a Troponin I (R145G) Mutation Associated with Familial Hypertrophic Cardiomyopathy

Lang¹,

Gomes²,

Zhao³

et al. 2002

Journal of Biological Chemistry

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Familial hypertrophic cardiomyopathy has been associated with several mutations in the gene encoding human cardiac troponin I (HCTnI). A missense mutation in the inhibitory region of TnI replaces an arginine residue at position 145 with a glycine and cosegregates with the disease. Results from several assays indicate that the inhibitory function of HCTnI R145G is significantly reduced. When HCTnI R145G was incorporated into whole troponin, Tn R145G (HCTnT⅐HCTnI R145G ⅐HCTnC), only partial inhibition of the actin-tropomyosin-myosin ATPase activity was observed in the absence of Ca 2؉ compared with wild type Tn (HCTnT⅐HCTnI⅐HCTnC). Maximal activation of actin-tropomyosin-myosin ATPase in the presence of Ca 2؉ was also decreased in Tn R145G when compared with Tn. Using skinned cardiac muscle fibers, we determined that in comparison with the wild type complex 1) the complex containing HCTnI R145G only inhibited 84% of Ca 2؉ -unregulated force, 2) the recovery of Ca 2؉ -activated force was decreased, and 3) there was a significant increase in the Ca 2؉ sensitivity of force development. Computer modeling of troponin C and I variables predicts that the primary defect in TnI caused by these mutations would lead to diastolic dysfunction. These results suggest that severe diastolic dysfunction and somewhat decreased contractility would be prominent clinical features and that hypertrophy could arise as a compensatory mechanism. Familial hypertrophic cardiomyopathy (FHC)1 has been linked to mutations in genes of nine different sarcomeric proteins. These mutations have been found in the genes for ␣-myosin heavy chain (1), cardiac myosin essential light chain and cardiac myosin regulatory light chain (2), ␣-tropomyosin, cardiac troponin T (TnT) (3), cardiac myosin-binding protein C (4, 5), troponin I (TnI) (6), ␣-actin (7), as well as titin (8), and possibly troponin C (TnC) (9). This disease has recently gained significant attention due to several highly publicized reports of sudden death and fainting spells in young athletes who were asymptomatic and otherwise healthy individuals. In general, patients with FHC demonstrate an increase in heart muscle mass and sometimes an irregular echocardiogram (10). Kimura et al. (6) reported five missense mutations in TnI, R145G, R145Q, R162W, G203S, and K206Q, that cosegregate with FHC (Fig. 1). Three other TnI FHC mutants (S199N, Lys-183 deletion, and an exon 8 deletion mutant encompassing the stop codon of the cardiac TnI gene) have recently been discovered (11, 12). Functionally TnI is the inhibitory subunit of the troponin (Tn) complex that controls the interaction between actin and myosin in a Ca 2ϩ -dependent manner (13-15). Studies using proteolytic fragments of fast skeletal TnI identified the central TnI sequence (residues 96 -116) as being responsible for its inhibitory activity. Residues 104 -115 of fast skeletal TnI (comparable to residues 136 -147 in cardiac TnI) formed the minimum sequence necessary for inhibition of muscle contraction (16 -19). Two of these mutations occ...

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Cardiac Troponin I Phosphorylation Increases the Rate of Cardiac Muscle Relaxation

Cited by 293 publications

References 36 publications

Decreased polycystin 2 expression alters calcium-contraction coupling and changes β-adrenergic signaling pathways

Decreased polycystin 2 expression alters calcium-contraction coupling and changes β-adrenergic signaling pathways

Reconstitution of skinned cardiac fibres with human recombinant cardiac troponin‐I mutants and troponin‐C

Functional Analysis of a Troponin I (R145G) Mutation Associated with Familial Hypertrophic Cardiomyopathy

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