Junctin is a prominent regulator of contractility in cardiomyocytes

Fan, Guo-Chang; Yuan, Qunying; Zhao, Wen; Chu, Guoxiang; Kranias, Evangelia G.

doi:10.1016/j.bbrc.2006.11.093

Cited by 21 publications

(15 citation statements)

References 15 publications

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“…This effect may explain the reduced SR Ca load and the lower Ca spark frequency in junctin-overexpressing mice (18). In line with these findings, overexpression of junctin in isolated myocytes was associated with a prolonged relaxation (9,10). In contrast, the deletion of junctin was accompanied by a higher SR Ca content and a hastened relaxation in knockout mice (45).…”

Section: Discussionsupporting

confidence: 70%

“…In contrast, the overexpression of triadin in single-transgenic mice was associated with a 73% downregulation of junctin, limiting the interpretation of physiological alterations, which were thus ascribed directly to triadin. Moreover, the separate investigation of both models is stringently necessary because recent studies have revealed new insight into the important role of junctin in regulating SR Ca homeostasis and contractility (9,10,45). Thus characterization of the present co-overexpression model allowed a more precise definition of triadin function in SR Ca signaling.…”

Section: Discussionmentioning

confidence: 94%

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Triadin is a critical determinant of cellular Ca cycling and contractility in the heart

Kirchhefer¹,

Klimas²,

Baba³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Triadin is involved in the regulation of cardiac excitation-contraction coupling. However, the extent of its contribution to the regulation of sarcoplasmic reticulum (SR) Ca release remains unclear, because overexpression of triadin in single-transgenic mice was associated with the downregulation of its homologous protein, junctin. In the present study, this problem was circumvented by cross-breeding of mice with heart-directed overexpression of triadin and junctin (JxT). This resulted in a stable approximately threefold expression of total triadin but unchanged junctin protein. Transgenic mice exhibited cardiac hypertrophy and structural abnormalities of myofibrils. Measurement of cardiac function by echocardiography and edge detection in myocytes revealed an impaired relaxation in JxT mice. The stimulation of beta-adrenergic receptors resulted in a depressed contractility and an impaired relaxation in catheterized hearts and myocytes of JxT mice. The use of a maximum stimulation frequency (5 Hz) was associated with both a lower shortening and relengthening in isolated myocytes of JxT mice. The contractile effects in JxT myocytes were paralleled by similar changes of the intracellular Ca concentration ([Ca](i)) peak amplitude and Ca transient decay kinetics at basal conditions, under administration of isoproterenol, and with high-frequency stimulation. Finally, we found a higher caffeine-induced [Ca](i) peak amplitude in JxT myocytes. Our data show that the stable expression of triadin, independent of junctin expression, resulted in cardiac hypertrophy, prolonged basal relaxation, a depressed response to beta-adrenergic agonists, and altered Ca transients. Thus the maintenance of triadin expression is essential for normal SR Ca cycling and contractile function.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 94%

Triadin is a critical determinant of cellular Ca cycling and contractility in the heart

Kirchhefer¹,

Klimas²,

Baba³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…Changes in expression of other proteins (Kirchhefer et al, 2003, Hong et al, 2002) as well as in the cardiac t-tubule/SR junction (Franzini-Armstrong et al, 2005) must also impact on Ca 2+ release. An inhibitory effect of junctin on cardiac RyR2 channels is also indicated by enhanced Ca 2+ release in cardiac myocytes from junctin knock-down mice (Yuan et al, 2007) and with acute down-regulation (Fan et al, 2007) although both knockdown and overexpression can also induce changes in expression levels of other proteins (Wang et al, 2008). …”

Section: Discussionmentioning

confidence: 99%

Junctin and triadin each activate skeletal ryanodine receptors but junctin alone mediates functional interactions with calsequestrin

Wei

Gallant

Dulhunty

et al. 2009

The International Journal of Biochemistry & Cell Biology

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Summary Normal Ca2+ signalling in skeletal muscle depends on the membrane associated proteins triadin and junctin and their ability to mediate functional interactions between the Ca2+ binding protein calsequestrin and the type 1 ryanodine receptor in the lumen of the sarcoplasmic reticulum. This important mechanism conserves intracellular Ca2+ stores, but is poorly understood. Triadin and junctin share similar structures and are lumped together in models of interactions between skeletal muscle calsequestrin and ryanodine receptors, however their individual roles have not been examined at a molecular level. We show here that purified skeletal ryanodine receptors are similarly activated by purified triadin or purified junctin added to their luminal side, although a lack of competition indicated that the proteins act at independent sites. Surprisingly, triadin and junctin differed markedly in their ability to transmit information between skeletal calsequestrin and ryanodine receptors. Purified calsequestrin inhibited junctin/triadin-associated, or junctin-associated, ryanodine receptors and the calsequestrin re-associated channel complexes were further inhibited when luminal Ca2+ fell from 1mM to ≤100μM, as seen with native channels (containing endogenous calsequestrin/triadin/junctin). In contrast, skeletal calsequestrin had no effect on the triadin/ryanodine receptor complex and the channel activity of this complex increased when luminal Ca2+ fell, as seen with purified channels prior to triadin/calsequestrin re-association. Therefore in this cell free system, junctin alone mediates signals between luminal Ca2+, skeletal calsequestrin and skeletal ryanodine receptors and may curtail resting Ca2+ leak from the sarcoplasmic reticulum. We suggest that triadin serves a different function which may dominate during excitation- contraction coupling.

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“…Rat ventricular myocytes were isolated from adult male Sprague-Dawley rats (6–8-wk old) and plated on laminin-coated glass coverslips or dishes, as described previously [24]. Recombinant adenoviruses Ad.GFP encoding GFP, Ad.Hsp20 containing both Hsp20 and GFP, and Ad.Hsp20-AS containing both antisense Hsp20 and GFP were generated by using the AdEasy-1 expression system, as described previously [21, 22].…”

Section: Methodsmentioning

confidence: 99%

Overexpression of Hsp20 prevents endotoxin-induced myocardial dysfunction and apoptosis via inhibition of NF-κB activation

Wang

Zingarelli

O’Connor

et al. 2009

Journal of Molecular and Cellular Cardiology

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The occurrence of cardiovascular dysfunction in sepsis is associated with a significantly increased mortality rate of 70% to 90% compared with 20% in septic patients without cardiovascular impairment. Thus, rectification or blockade of myocardial depressant factors should partly ameliorate sepsis progression. Heat shock protein 20 (Hsp20) has been shown to enhance myocardial contractile function and protect against doxorubicin-induced cardiotoxicity. To investigate the possible role of Hsp20 in sepsis-mediated cardiac injury, we first examined the expression profiles of five major Hsps in response to lipopolysaccharide (LPS) challenge, and observed that only the expression of Hsp20 was downregulated in LPS-treated myocardium, suggesting that this decrease might be one of mechanisms contributing to LPS-induced cardiovascular defects. Further studies using loss-offunction and gain-of function approaches in adult rat cardiomyocytes verified that reduced Hsp20 levels were indeed correlated with the impaired contractile function. In fact, overexpression of Hsp20 significantly enhanced cardiomyocyte contractility upon LPS treatment. Moreover, after administration of LPS (25μg/g) in vivo, Hsp20 transgenic mice (10-fold overexpression) displayed: 1) an improvement in myocardial function; 2) reduced the degree of cardiac apoptosis; and 3) decreased NF-κB activity, accompanied with reduced myocardial cytokines IL-1β and TNF-α production, compared to the LPS-treated non-transgenic littermate controls. Thus, the increases in Hsp20 levels can protect against LPS-induced cardiac apoptosis and dysfunction, associated with inhibition of NF-κB activity, suggesting that Hsp20 may be a new therapeutic agent for the treatment of sepsis.

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Junctin is a prominent regulator of contractility in cardiomyocytes

Cited by 21 publications

References 15 publications

Triadin is a critical determinant of cellular Ca cycling and contractility in the heart

Triadin is a critical determinant of cellular Ca cycling and contractility in the heart

Junctin and triadin each activate skeletal ryanodine receptors but junctin alone mediates functional interactions with calsequestrin

Overexpression of Hsp20 prevents endotoxin-induced myocardial dysfunction and apoptosis via inhibition of NF-κB activation

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