Pathophysiological Significance of T-type Ca2+ Channels: Transcriptional Regulation of T-type Ca2+ Channel — Regulation of CACNA1H by Neuron-Restrictive Silencer Factor

Kuwahara, Koichiro; Takano, Makoto; Nakao, Kazuwa

doi:10.1254/jphs.fmj05002x4

Cited by 20 publications

(19 citation statements)

References 15 publications

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“…Although activation and deactivation of T-type Ca 2ϩ channel gene expression has been observed in many pathological conditions and under various stimuli (4, 26, 35), transcription factors involved in such gene regulation are just beginning to emerge. For instance, repressor element-1 silencing transcription factor, also known as neuron-restrictive silencer factor (15,36), early growth response factor-1 (ERG1) (12), transcription factor GATA4 (28), cardiac homeobox transcription factor Csx/Nkx2.5 (38), and LEF1/␤-catenin complex (39) have been reported to function as a transcriptional regulator of ␣ 1H . However, it is of note that, among these identified transcription factors, ERG1, GATA4, NKX2.5, as well as ␤-catenin signaling have been reported to be regulated by hypoxia (13,25,28,41).…”

Section: Discussionmentioning

confidence: 99%

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Transcriptional regulation of α_1H T-type calcium channel under hypoxia

Hassan

Zhou

Liu

et al. 2014

American Journal of Physiology-Cell Physiology

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scriptional regulation of ␣1H T-type calcium channel under hypoxia. Am J Physiol Cell Physiol 307: C648 -C656, 2014. First published August 6, 2014; doi:10.1152/ajpcell.00210.2014.-The low-voltageactivated T-type Ca 2ϩ channels play an important role in mediating the cellular responses to altered oxygen tension. Among three T-type channel isoforms, ␣1G, ␣1H, and ␣1I, only ␣1H was found to be upregulated under hypoxia. However, mechanisms underlying such hypoxia-dependent isoform-specific gene regulation remain incompletely understood. We, therefore, studied the hypoxia-dependent transcriptional regulation of ␣1G and ␣1H gene promoters with the aim to identify the functional hypoxia-response elements (HREs). In rat pulmonary artery smooth muscle cells (PASMCs) and pheochromocytoma (PC12) cells after hypoxia (3% O2) exposure, we observed a prominent increase in ␣ 1H mRNA at 12 h along with a significant rise in ␣ 1H-mediated T-type current at 24 and 48 h. We then cloned two promoter fragments from the 5=-flanking regions of rat ␣ 1G and ␣1H gene, 2,000 and 3,076 bp, respectively, and inserted these fragments into a luciferase reporter vector. Transient transfection of PASMCs and PC12 cells with these recombinant constructs and subsequent luciferase assay revealed a significant increase in luciferase activity from the reporter containing the ␣1H, but not ␣1G, promoter fragment under hypoxia. Using serial deletion and point mutation analysis strategies, we identified a functional HRE at site Ϫ1,173CACGCϪ1,169 within the ␣ 1H promoter region. Furthermore, an electrophoretic mobility shift assay using this site as a DNA probe demonstrated an increased binding activity to nuclear protein extracts from the cells after hypoxia exposure. Taken together, these findings indicate that hypoxia-induced ␣ 1H upregulation involves binding of hypoxia-inducible factor to an HRE within the ␣1H promoter region.T-type calcium channel; gene expression; hypoxia; hypoxia-response element HYPOXIA IS AN ESSENTIAL and critical pathological component of many pulmonary disorders, including acute lung injury, chronic obstructive pulmonary disease, and pulmonary hypertension. One of the most important responses to hypoxia in the pulmonary vasculature is a change in intracellular calcium homeostasis. Smooth muscle cells in pulmonary arteries, i.e., pulmonary artery smooth muscle cells (PASMCs), and endothelial cell in the microvessels, i.e., pulmonary microvascular endothelial cells (PMVECs), are both equipped with voltage-gated Ca 2ϩ channels. The two major classes of voltage-gated Ca 2ϩ channels are differentiated by their electrophysiological properties: high-voltage-activated channels, which include the L-, N-, P/Q-, and R-subtypes, and low-voltage-activated channels, also known as T-type channels. In addition to their distinct voltage dependence of activation, T-type channels also exhibit a unique rapid inactivation and slow deactivation time course (29). Functionally, the L-type channel has long been considered the predominant source of C...

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Section: Discussionmentioning

confidence: 99%

“…Changes in T-type Ca 2ϩ channel expression have been observed during organ development as well as under various pathological states (15,27). However, little is known about the transcriptional regulation of the T-type Ca 2ϩ channel gene expression.…”

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Transcriptional regulation of α_1H T-type calcium channel under hypoxia

Hassan

Zhou

Liu

et al. 2014

American Journal of Physiology-Cell Physiology

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“…Transcription factors proposed to regulate Ca v 3.2 include hypoxia-inducible factor (HIF)-1␣ (7), neuron restrictive silencer factor (25,51), and Csx/Nkx2.5 (46). The effects of hypoxia on T-type calcium channels in renal proximal tubule (1), neurons (20, 21), PC12 cells (7), and in a heterologous expression system (11) implicate Ca v 3.2 as the primary hypoxia sensitive ␣-subunit.…”

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T-type calcium channels are regulated by hypoxia/reoxygenation in ventricular myocytes

Pluteanu

Cribbs

2009

American Journal of Physiology-Heart and Circulatory Physiology

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Pluteanu F, Cribbs LL. T-type calcium channels are regulated by hypoxia/reoxygenation in ventricular myocytes. Am J Physiol Heart Circ Physiol 297: H1304 -H1313, 2009. First published August 7, 2009 doi:10.1152/ajpheart.00528.2009.-Low-voltageactivated calcium channels are reexpressed in ventricular myocytes in pathological conditions associated with hypoxic episodes, but a direct relation between oxidative stress and T-type channel function and regulation in cardiomyocytes has not been established. We aimed to investigate low-voltage-activated channel regulation under oxidative stress in neonatal rat ventricular myocytes. RT-PCR measurements of voltage-gated Ca 2ϩ (Cav)3.1 and Cav3.2 mRNA levels in oxidative stress were compared with whole cell patch-clamp recordings of T-type calcium current. The results indicate that hypoxia reduces T-type current density at Ϫ30 mV (the hallmark of this channel) based on the shift of the voltage dependence of activation to more depolarized values and downregulation of Ca v3.1 at the mRNA level. Upon reoxygenation, both Ca v3.1 mRNA levels and the voltage dependence of total T-type current are restored, although differently for activation and inactivation. Using Ni 2ϩ , we distinguished different effects of hypoxia/reoxygenation on the two current components. Long-term incubation in the presence of 100 M CoCl 2 reproduced the effects of hypoxia on T-type current activation and inactivation, indicating that the chemically induced oxidative state is sufficient to alter T-type calcium current activity, and that hypoxia-inducible factor-1␣ is involved in Ca v3.1 downregulation. Our results demonstrate that Ca v3.1 and Cav3.2 T-type calcium channels are differentially regulated by hypoxia/reoxygenation injury, and, therefore, they may serve different functions in the myocyte in response to hypoxic injury. low-voltage-activated calcium channel; oxidative stress; cardiomyocytes SINCE THE INITIAL BIOPHYSICAL (34) and molecular characterization (5, 27, 36) of low-voltage-activated T-type calcium currents in heart and neurons, these channels have been studied in various systems and pathological conditions. T-type currents are reexpressed in the adult hypertrophied ventricle and in postmyocardial infarction (18), in the monocrotaline model of pulmonary hypertension and heart failure (24, 44), and in vitro in adult ventricular myocytes exposed to 10% FBS (9) and endothelin-1 (19), relating the T-type current to the pathology rather than to normal physiological function of the myocytes. The mechanisms for regulation of the T-type channels are incompletely characterized, largely due to the lack of specific inhibitors and the presence of the more robust L-type and store-operated calcium channels, which make it difficult to isolate T-type Ca 2ϩ channel functions, such as secretion (29), excitation (52), or transcription regulation (4).

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“…29 One of the major sources of Ca 2+ influx in excitable cells is voltage-gated Ca 2+ channels, which have been classified into several types: L-(long lasting), T-(transient), N-(neuronal), P/Q-(Purkinje) and R-(residual-drug resistant); generally, cardiac myocytes express only the L-and T-types. Ltype Ca 2+ channels predominate in mature cardiac myocytes and are crucially involved in excitation-contraction coupling.…”

Section: T-type Ca 2+ Channelsmentioning

confidence: 99%

Role of NRSF/REST in the Regulation of Cardiac Gene Expression and Function

Kuwahara

2013

Circ J

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Alterations in the cardiac gene program affect both cardiac structure and function, and play a key role in the progression of pathological cardiac remodeling and heart failure. For instance, reactivation of fetal cardiac genes in adults is a consistent feature of cardiac hypertrophy and heart failure. Investigation of the transcriptional regulation of cardiac genes revealed a transcriptional repressor, neuron-restrictive silencer factor (NRSF), also called repressor element-1 silencing factor (REST), to be an important regulator of multiple fetal cardiac genes. Inhibition of NRSF in the heart leads to cardiac dysfunction and sudden arrhythmic death accompanied by re-expression of various fetal genes, including those encoding fetal ion channels, such as the HCN channels and T-type Ca 2+ channels. These findings shed light on the crucial regulatory function of NRSF in the heart and its importance for maintaining normal cardiac integrity. (Circ J 2013; 77: 2682 -2686

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Pathophysiological Significance of T-type Ca2+ Channels: Transcriptional Regulation of T-type Ca2+ Channel — Regulation of CACNA1H by Neuron-Restrictive Silencer Factor

Cited by 20 publications

References 15 publications

Transcriptional regulation of α_1H T-type calcium channel under hypoxia

Transcriptional regulation of α_1H T-type calcium channel under hypoxia

T-type calcium channels are regulated by hypoxia/reoxygenation in ventricular myocytes

Role of NRSF/REST in the Regulation of Cardiac Gene Expression and Function

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Pathophysiological Significance of T-type Ca2+ Channels: Transcriptional Regulation of T-type Ca2+ Channel — Regulation of CACNA1H by Neuron-Restrictive Silencer Factor

Cited by 20 publications

References 15 publications

Transcriptional regulation of α1H T-type calcium channel under hypoxia

Transcriptional regulation of α1H T-type calcium channel under hypoxia

T-type calcium channels are regulated by hypoxia/reoxygenation in ventricular myocytes

Role of NRSF/REST in the Regulation of Cardiac Gene Expression and Function

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Transcriptional regulation of α_1H T-type calcium channel under hypoxia

Transcriptional regulation of α_1H T-type calcium channel under hypoxia