NFATc3 Regulates Kv2.1 Expression in Arterial Smooth Muscle

Amberg, Gregory C.; Rossow, Charles F.; Navedo, Manuel F.; Santana, Luis Fernando

doi:10.1074/jbc.m408789200

Cited by 99 publications

(129 citation statements)

References 46 publications

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“…Interestingly, Kv2.1 is an oxygen sensitive potassium channel and its dysfunction contributes to the pathogenesis of PAH. 33 Although activation of NFATc3 controls the excitability of cerebral arterial smooth muscle cell by downregulation of Kv2.1, 34 little is known about the relationship between NFATc3 and Kv2.1 in PAH. Additionally, the overexpression of ET-1 induced by hypoxia leads to [Ca 2C ] mobilization and stimulates RhoA/ROK activity.…”

Section: Nfatc3mentioning

confidence: 99%

The role of nuclear factor of activated T cells in pulmonary arterial hypertension

et al. 2017

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Nuclear factor of activated T cells (NFAT) was first identified as a transcription factor about 3 decades ago and was not well studied until the development of immunosuppressant. Numerous studies confirm that calcineurin/NFAT signaling is very important in the development of vasculature and cardiovascular system during embryogenesis and is involved in the development of vascular diseases such as hypertension, atherosclerosis and restenosis. Recent studies demonstrated that NFAT proteins also regulate immune response and vascular cells in the pulmonary microenvironment. In this review, we will discuss how different NFAT isoforms contribute to pulmonary vascular remodeling and potential new therapeutic targets for treating pulmonary arterial hypertension.

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Section: Nfatc3mentioning

confidence: 99%

The role of nuclear factor of activated T cells in pulmonary arterial hypertension

et al. 2017

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“…Decreased Kv channel function depolarizes arterial smooth muscle, which indirectly increases LTCC function (12). The mechanism by which these channels activate calcineurin in smooth muscle is unclear (11,13).In this study, we examined the role of PKC␣ and Ca 2ϩ sparklet activity in the development of arterial dysfunction during hypertension. Our data suggest that increased Ca 2ϩ influx via persistent Ca 2ϩ sparklet sites underlies increased arterial [Ca 2ϩ ] i and myogenic tone during hypertension.…”

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confidence: 99%

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confidence: 99%

“…(iii) AngII activates the Ca 2ϩ -sensitive phosphatase calcineurin via LTCC Ca 2ϩ entry in hypertension. Calcineurin in turn dephosphorylates and hence activates the transcription factor NFATc3, decreasing the expression of voltage-gated K ϩ (Kv) channels in hypertensive arterial smooth muscle (11). Decreased Kv channel function depolarizes arterial smooth muscle, which indirectly increases LTCC function (12).…”

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confidence: 99%

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The control of Ca ²⁺ influx and NFATc3 signaling in arterial smooth muscle during hypertension

Nieves‐Cintrón

Amberg

Navedo

et al. 2008

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

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Many excitable cells express L-type Ca 2؉ channels (LTCCs), which participate in physiological and pathophysiological processes ranging from memory, secretion, and contraction to epilepsy, heart failure, and hypertension. Clusters of LTCCs can operate in a PKC␣-dependent, high open probability mode that generates sites of sustained Ca 2؉ influx called ''persistent Ca 2؉ sparklets.'' Although increased LTCC activity is necessary for the development of vascular dysfunction during hypertension, the mechanisms leading to increased LTCC function are unclear. Here, we tested the hypothesis that increased PKC␣ and persistent Ca 2؉ sparklet activity contributes to arterial dysfunction during hypertension. We found that PKC␣ and persistent Ca 2؉ sparklet activity is indeed increased in arterial myocytes during hypertension. Furthermore, in human arterial myocytes, PKC␣-dependent persistent Ca 2؉ sparklets activated the prohypertensive calcineurin/NFATc3 signaling cascade. These events culminated in three hallmark signs of hypertensionassociated vascular dysfunction: increased Ca 2؉ entry, elevated arterial [Ca 2؉ ]i, and enhanced myogenic tone. Consistent with these observations, we show that PKC␣ ablation is protective against the development of angiotensin II-induced hypertension. These data support a model in which persistent Ca 2؉ sparklets, PKC␣, and calcineurin form a subcellular signaling triad controlling NFATc3-dependent gene expression, arterial function, and blood pressure. Because of the ubiquity of these proteins, this model may represent a general signaling pathway controlling gene expression and cellular function.angiotensin II ͉ myogenic tone ͉ sparklets ͉ transcription factors ͉ voltage-gated calcium channels A rterial tone is elevated during hypertension, increasing the probability of stroke, coronary artery disease, cardiac hypertrophy, and renal failure (1, 2). Although the etiology of arterial dysfunction during hypertension is unclear, multiple studies suggest that increased L-type Ca 2ϩ channel (LTCC) activity in arterial smooth muscle is a major contributor to this pathological change (3, 4). However, the mechanisms and functional implications of increased Ca 2ϩ influx via LTCCs remain unclear.In normotensive arterial smooth muscle, the opening of LTCCs produces local elevations in [Ca 2ϩ ] i called ''Ca 2ϩ sparklets'' (5, 6). Two modes of Ca 2ϩ sparklet activity have been identified (6-8). Low-activity Ca 2ϩ sparklets are produced by brief random openings of LTCCs that result in limited Ca 2ϩ influx. In contrast, long openings of LTCCs associated with PKC␣ produce high activity, persistent Ca 2ϩ sparklets that create regions of sustained Ca 2ϩ influx. Low-and high-activity, persistent Ca 2ϩ sparklets are produced by the opening of a single or a small cluster of LTCCs. PKC␣ is required for persistent, but not for low-activity, Ca 2ϩ sparklets. Under physiological conditions, Ca 2ϩ entry and global [Ca 2ϩ ] i and, thus, contraction are regulated by low-activity and PKC␣-dependent persistent Ca 2ϩ...

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“…Vasoconstrictors such as angiotensin II (6) and UTP (7) increase LTCC activity by causing membrane depolarization (8) and activation of PKC (1). Using conventional imaging and electrophysiological techniques, a generally accepted model has evolved in which membrane depolarization and PKC increase the open probability of individual LTCCs; stochastic activation of single LTCCs increases Ca 2ϩ influx, culminating in increased intracellular free calcium concentration ([Ca 2ϩ ] i ) and contraction (9)(10)(11). A similar model has been proposed in heart (12).…”

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confidence: 99%

Constitutively active L-type Ca ²⁺ channels

Navedo

Amberg

Votaw

et al. 2005

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

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367

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Ca 2؉ influx through L-type Ca 2؉ channels (LTCCs) influences numerous physiological processes ranging from contraction in muscle and memory in neurons to gene expression in many cell types. However, the spatiotemporal organization of functional LTCCs has been nearly impossible to investigate because of methodological limitations. Here, we examined LTCC function with high temporal and spatial resolution using evanescent field fluorescence microscopy. Surprisingly, we found that LTCCs operated in functionally organized clusters, not necessarily as individual proteins. Furthermore, LTCC function in these clusters does not appear to be controlled by simple stochastic gating but instead by a PKCdependent switch mechanism. This work suggests that resting intracellular free calcium concentration in arterial myocytes is predominantly controlled by this process in combination with rare voltage-dependent openings of individual LTCCs. We propose that Ca 2؉ influx via persistent LTCCs may be an important mechanism regulating steady-state local and global Ca 2؉ signals.evenescent field microscopy ͉ smooth muscle ͉ sparklets

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NFATc3 Regulates Kv2.1 Expression in Arterial Smooth Muscle

Cited by 99 publications

References 46 publications

The role of nuclear factor of activated T cells in pulmonary arterial hypertension

The role of nuclear factor of activated T cells in pulmonary arterial hypertension

The control of Ca ²⁺ influx and NFATc3 signaling in arterial smooth muscle during hypertension

Constitutively active L-type Ca ²⁺ channels

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NFATc3 Regulates Kv2.1 Expression in Arterial Smooth Muscle

Cited by 99 publications

References 46 publications

The role of nuclear factor of activated T cells in pulmonary arterial hypertension

The role of nuclear factor of activated T cells in pulmonary arterial hypertension

The control of Ca 2+ influx and NFATc3 signaling in arterial smooth muscle during hypertension

Constitutively active L-type Ca 2+ channels

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The control of Ca ²⁺ influx and NFATc3 signaling in arterial smooth muscle during hypertension

Constitutively active L-type Ca ²⁺ channels