Crosstalk between L-type calcium channels and ZnT-1, a new player in rate-dependent cardiac electrical remodeling

Beharier, Ofer; Etzion, Yoram; Katz, Amos; Friedman, Hani; Tenbosh, Nir; Zacharish, Saar; Bereza, Sergiy; Goshen, Uri; Moran, Arie

doi:10.1016/j.ceca.2006.11.007

Cited by 40 publications

(79 citation statements)

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“…Recently, we demonstrated that expression of ZnT-1 is modulated in cardiomyocytes in parallel to documented alterations in LTCC function. We observed that both rapid electrical pac-ing in rat atria in vivo, as well as in neonatal cardiomyocytes in primary culture, enhanced ZnT-1 expression and reduced Ca 2ϩ influx through LTCCs (31). Furthermore, we showed that the inhibitory effect of rapid pacing on LTCC function was antagonized by silencing the expression of ZnT-1 (31).…”

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confidence: 56%

“…Furthermore, we showed that the inhibitory effect of rapid pacing on LTCC function was antagonized by silencing the expression of ZnT-1 (31). Analysis of human atrial samples collected during heart surgery revealed increased expression of ZnT-1 in patients suffering from atrial fibrillation as compared with patients in sinus rhythm (31) implying a role for ZnT-1 in the LTCC dysfunction that is believed to play an important role in the pathophysiology of this common arrhythmia (9,41).…”

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confidence: 90%

“…ZnT-1 is expressed in most tissues, with high levels of expression observed primarily in the brain, the pancreas, the testes, and the heart (37)(38)(39). ZnT-1 inhibition of LTCC activity has recently been confirmed in several cell types (30,31,40). For example, silencing the expression of endogenous ZnT-1 in neurons was shown to markedly increase Ca 2ϩ influx via the LTCC, thereby enhancing synaptic release (40).…”

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confidence: 99%

“…ZnT-1 decreases the current amplitude of LTCCs in Xenopus oocytes without altering the total expression of the Cav1.2 ␣ 1 -subunit or the steady-state activation or the inactivation kinetics of the LTCC current (31). Attempts to demonstrate an interaction between ZnT-1 and the LTCC ␣ 1 -subunit were unsuccessful (30).…”

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confidence: 99%

“…Zinc transporter 1 (ZnT-1) was recently identified as an endogenous modulator of LTCC function (30,31). This transmembrane protein has been investigated mainly in the context of zinc metabolism and has been shown to confer resistance to zinc toxicity (32)(33)(34)(35)(36).…”

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confidence: 99%

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Molecular Basis for Zinc Transporter 1 Action as an Endogenous Inhibitor of L-type Calcium Channels

Levy

Beharier

Etzion

et al. 2009

Journal of Biological Chemistry

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The L-type calcium channel (LTCC) has a variety of physiological roles that are critical for the proper function of many cell types and organs. Recently, a member of the zinc-regulating family of proteins, ZnT-1, was recognized as an endogenous inhibitor of the LTCC, but its mechanism of action has not been elucidated. In the present study, using two-electrode voltage clamp recordings in Xenopus oocytes, we demonstrate that ZnT-1-mediated inhibition of the LTCC critically depends on the presence of the LTCC regulatory ␤-subunit. Moreover, the ZnT-1-induced inhibition of the LTCC current is also abolished by excess levels of the ␤-subunit. An interaction between ZnT-1 and the ␤-subunit, as demonstrated by co-immunoprecipitation and by fluorescence resonance energy transfer, is consistent with this result. Using surface biotinylation and total internal reflection fluorescence microscopy in HEK293 cells, we show a ZnT-1-dependent decrease in the surface expression of the pore-forming ␣ 1 -subunit of the LTCC. Similarly, a decrease in the surface expression of the ␣ 1 -subunit is observed following up-regulation of the expression of endogenous ZnT-1 in rapidly paced cultured cardiomyocytes. We conclude that ZnT-1-mediated inhibition of the LTCC is mediated through a functional interaction of ZnT-1 with the LTCC ␤-subunit and that it involves a decrease in the trafficking of the LTCC ␣ 1 -subunit to the surface membrane.

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Molecular Basis for Zinc Transporter 1 Action as an Endogenous Inhibitor of L-type Calcium Channels

Levy

Beharier

Etzion

et al. 2009

Journal of Biological Chemistry

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An increase in intercellular crosstalk and electrotonic coupling between cardiomyocytes and nonmyocytes reshapes the electrical conduction in the metabolic heart characterized by short QT intervals in ECGs

Billur,

Olgar,

Durak

et al. 2023

Cell Biochemistry & Function

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Cardiac conduction abnormalities are disorders in metabolic syndrome (MetS), however, their mechanisms are unknown. Although ventricular arrhythmia reflects the changes in QT‐interval of electrocardiograms associated with the changes in cardiomyocyte action potential durations (APDs), recent studies emphasize role of intercellular crosstalk between cardiomyocytes and nonmyocytes via passive (electrotonic)‐conduction. Therefore, considering the possible increase in intercellular interactions of nonmyocytes with cardiomyocytes, we hypothesized an early‐cardiac‐remodeling characterized by short QT‐interval via contributions and modulations of changes by nonmyocytes to the ventricular APs in an early‐stage MetS hearts. Following the feeding of 8‐week‐old rats with a high‐sucrose diet (32%; MetS rats) and validation of insulin resistance, there was a significant increase in heart rate and changes in the electrical characteristics of the hearts, especially a shortening in action potential (AP) duration of the papillary muscles. The patch‐clamp analysis of ventricular cardiomyocytes showed an increase in the Na+‐channel currents while there were decreases in l‐type Ca2+‐channel (LTCC) currents with unchanged K+‐channel currents. There was an increase in the phosphorylated form of connexin 43 (pCx43), mostly with lateral localization on sarcolemma, while its unphosphorylated form (Cx43) exhibited a high degree of localization within intercalated discs. A high‐level positively‐stained α‐SMA and CD68 cells were prominently localized and distributed in interfibrillar spaces of the heart, implying the possible contributions of myofibroblasts and macrophages to both shortened APDs and abnormal electrical conduction in MetS hearts. Our data propose a previously unrecognized pathway for SQT induction in the heart. This pathway includes not only the contribution of short ventricular‐APDs via ionic mechanisms but also increasing contributions of the electrotonic‐cardiomyocyte depolarization, spontaneous electrical activity‐associated fast heterogeneous impulse conduction in the heart via increased interactions and relocations between cardiomyocytes and nonmyocytes, which may be an explanation for the development of an SQT in early‐cardiac‐remodeling.

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Proarrhythmic Atrial Calcium Cycling in the Diseased Heart

Voigt

Nattel

Dobrev

2012

Advances in Experimental Medicine and Biology

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During the last decades Ca(2+) has been found to play a crucial role in cardiac arrhythmias associated with heart failure and a number of congenital arrhythmia syndromes. Recent studies demonstrated that altered atrial Ca(2+) cycling may promote the initiation and maintenance of atrial fibrillation, the most common clinical arrhythmia that contributes significantly to population morbidity and mortality. This article describes physiological Ca(2+) cycling mechanisms in atrial cardiomyocytes and relates them to fundamental cellular proarrhythmic mechanisms involving Ca(2+) signaling abnormalities in the atrium during atrial fibrillation.

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Crosstalk between L-type calcium channels and ZnT-1, a new player in rate-dependent cardiac electrical remodeling

Cited by 40 publications

References 50 publications

Molecular Basis for Zinc Transporter 1 Action as an Endogenous Inhibitor of L-type Calcium Channels

Molecular Basis for Zinc Transporter 1 Action as an Endogenous Inhibitor of L-type Calcium Channels

An increase in intercellular crosstalk and electrotonic coupling between cardiomyocytes and nonmyocytes reshapes the electrical conduction in the metabolic heart characterized by short QT intervals in ECGs

Proarrhythmic Atrial Calcium Cycling in the Diseased Heart

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