Subplasmalemmal hydrogen peroxide triggers calcium influx in gonadotropes

Dang, An K.; Chaplin, Nathan L.; Murtazina, Dilyara A.; Boehm, Ulrich; Clay, Colin M.; Amberg, Gregory C.

doi:10.1074/jbc.ra118.001830

Cited by 8 publications

(10 citation statements)

References 41 publications

(81 reference statements)

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“…2). This contrasts with what has been found in vertebrate arterial smooth muscle and gonadotropes (Chaplin and Amberg, 2012;Dang et al, 2018), but is consistent with reports of mitochondrial ROS elevation inhibiting L-VGCCs in cardiomyocytes (Scragg et al, 2008). Discrepancies in the concentration of ROS treatment between these studies and the one presented here could explain the opposing results.…”

Section: Rossupporting

confidence: 84%

“…Additionally, several studies have shown that neural excitability and synaptic plasticity are modified by ROS signaling (Yermolaieva et al, 2000;Kishida and Klann, 2007). More recently, a few studies have shown that function of VGCCs, including the L-type, is altered by increases in ROS above physiological concentrations (Todorovic and Jevtovic-Todorovic, 2014;Dang et al, 2018). However, we have a poor understanding of if and how physiological ROS signaling impacts activity-dependent fluctuations in neuronal calcium levels.…”

Section: Activity-dependent Calcium Signaling Regulates Ampar Transportmentioning

confidence: 99%

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Reactive Oxygen Species Modulate Activity-Dependent AMPA Receptor Transport in C. elegans

2020

Self Cite

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The AMPA subtype of synaptic glutamate receptors (AMPARs) plays an essential role in cognition. Their function, numbers, and change at synapses during synaptic plasticity are tightly regulated by neuronal activity. Although we know that long-distance transport of AMPARs is essential for this regulation, we do not understand the associated regulatory mechanisms of it. Neuronal transmission is a metabolically demanding process in which ATP consumption and production are tightly coupled and regulated. Aerobic ATP synthesis unavoidably produces reactive oxygen species (ROS), such as hydrogen peroxide, which are known modulators of calcium signaling. Although a role for calcium signaling in AMPAR transport has been described, there is little understanding of the mechanisms involved and no known link to physiological ROS signaling. Here, using realtime in vivo imaging of AMPAR transport in the intact C. elegans nervous system, we demonstrate that long-distance synaptic AMPAR transport is bidirectionally regulated by calcium influx and activation of calcium/calmodulin-dependent protein kinase II. Quantification of in vivo calcium dynamics revealed that modest, physiological increases in ROS decrease calcium transients in C. elegans glutamatergic neurons. By combining genetic and pharmacological manipulation of ROS levels and calcium influx, we reveal a mechanism in which physiological increases in ROS cause a decrease in synaptic AMPAR transport and delivery by modulating activity-dependent calcium signaling. Together, our results identify a novel role for oxidant signaling in the regulation of synaptic AMPAR transport and delivery, which in turn could be critical for coupling the metabolic demands of neuronal activity with excitatory neurotransmission.

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Section: Rossupporting

confidence: 84%

Section: Activity-dependent Calcium Signaling Regulates Ampar Transportmentioning

confidence: 99%

Reactive Oxygen Species Modulate Activity-Dependent AMPA Receptor Transport in C. elegans

2020

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“…Alternatively, it has been recognized to be one of the most promising drugs in a variety of pathophysiological disorders, such as inflammatory and neurodegenerative diseases, glioma, and cardiac failure [1,3,[5][6][7][8][9][10][11] aPO has been recently shown to ameliorate cardiac function (e.g., structural remodeling) in heart failure [6,7,[11][12][13]. Pituitary cells were previously demonstrated to be expressed in the activity of NOX [14,15]. aPO has been reported to blunt the progression of neuroendocrine alterations induced by social isolation, which were thought to be mainly through its inhibition of NOX activity [16].…”

Section: Introductionmentioning

confidence: 99%

Effective Accentuation of Voltage-Gated Sodium Current Caused by Apocynin (4′-Hydroxy-3′-methoxyacetophenone), a Known NADPH-Oxidase Inhibitor

Chuang

Cho

2021

Biomedicines

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Apocynin (aPO, 4′-Hydroxy-3′-methoxyacetophenone) is a cell-permeable, anti-inflammatory phenolic compound that acts as an inhibitor of NADPH-dependent oxidase (NOX). However, the mechanisms through which aPO can interact directly with plasmalemmal ionic channels to perturb the amplitude or gating of ionic currents in excitable cells remain incompletely understood. Herein, we aimed to investigate any modifications of aPO on ionic currents in pituitary GH3 cells or murine HL-1 cardiomyocytes. In whole-cell current recordings, GH3-cell exposure to aPO effectively stimulated the peak and late components of voltage-gated Na+ current (INa) with different potencies. The EC50 value of aPO required for its differential increase in peak or late INa in GH3 cells was estimated to be 13.2 or 2.8 μM, respectively, whereas the KD value required for its retardation in the slow component of current inactivation was 3.4 μM. The current–voltage relation of INa was shifted slightly to more negative potential during cell exposure to aPO (10 μM); however, the steady-state inactivation curve of the current was shifted in a rightward direction in its presence. Recovery of peak INa inactivation was increased in the presence of 10 μM aPO. In continued presence of aPO, further application of rufinamide or ranolazine attenuated aPO-stimulated INa. In methylglyoxal- or superoxide dismutase-treated cells, the stimulatory effect of aPO on peak INa remained effective. By using upright isosceles-triangular ramp pulse of varying duration, the amplitude of persistent INa measured at low or high threshold was enhanced by the aPO presence, along with increased hysteretic strength appearing at low or high threshold. The addition of aPO (10 μM) mildly inhibited the amplitude of erg-mediated K+ current. Likewise, in HL-1 murine cardiomyocytes, the aPO presence increased the peak amplitude of INa as well as decreased the inactivation or deactivation rate of the current, and further addition of ranolazine or esaxerenone attenuated aPO-accentuated INa. Altogether, this study provides a distinctive yet unidentified finding that, despite its effectiveness in suppressing NOX activity, aPO may directly and concertedly perturb the amplitude, gating and voltage-dependent hysteresis of INa in electrically excitable cells. The interaction of aPO with ionic currents may, at least in part, contribute to the underlying mechanisms through which it affects neuroendocrine, endocrine or cardiac function.

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“…This indicates that primary gonadotropes may have a higher capacity to rescue LH secretion in glucose-free conditions by relying on mitochondria. Subplasmalemmal mitochondria in gonadotropes contribute to GnRH-induced reactive oxygen species and Ca 2+ flux 61 , a mechanism which supports LH synthesis and secretion. Further, L-type calcium channels are closely associated with these sub-plasmalemmal mitochondria and appear coordinated with ROS generation by GnRH-induced NADPH oxidase activity 61 .…”

Section: Discussionmentioning

confidence: 99%

“…Subplasmalemmal mitochondria in gonadotropes contribute to GnRH-induced reactive oxygen species and Ca 2+ flux 61 , a mechanism which supports LH synthesis and secretion. Further, L-type calcium channels are closely associated with these sub-plasmalemmal mitochondria and appear coordinated with ROS generation by GnRH-induced NADPH oxidase activity 61 . This suggests overall that ion channel activation, GLUT1 activity, and ROS generation may be interconnected in eliciting LH secretion in response to GnRH receptor activation.…”

Section: Discussionmentioning

confidence: 99%

GLUT1-mediated glycolysis supports GnRH-induced secretion of luteinizing hormone from female gonadotropes

Nicholas

Knight

Tonsfeldt

et al. 2020

Sci Rep

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The mechanisms mediating suppression of reproduction in response to decreased nutrient availability remain undefined, with studies suggesting regulation occurs within the hypothalamus, pituitary, or gonads. By manipulating glucose utilization and GLUT1 expression in a pituitary gonadotrope cell model and in primary gonadotropes, we show GLUT1-dependent stimulation of glycolysis, but not mitochondrial respiration, by the reproductive neuropeptide GnRH. GnRH stimulation increases gonadotrope GLUT1 expression and translocation to the extracellular membrane. Maximal secretion of the gonadotropin Luteinizing Hormone is supported by GLUT1 expression and activity, and GnRH-induced glycolysis is recapitulated in primary gonadotropes. GLUT1 expression increases in vivo during the GnRH-induced ovulatory LH surge and correlates with GnRHR. We conclude that the gonadotropes of the anterior pituitary sense glucose availability and integrate this status with input from the hypothalamus via GnRH receptor signaling to regulate reproductive hormone synthesis and secretion.

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Subplasmalemmal hydrogen peroxide triggers calcium influx in gonadotropes

Cited by 8 publications

References 41 publications

Reactive Oxygen Species Modulate Activity-Dependent AMPA Receptor Transport in C. elegans

Reactive Oxygen Species Modulate Activity-Dependent AMPA Receptor Transport in C. elegans

Effective Accentuation of Voltage-Gated Sodium Current Caused by Apocynin (4′-Hydroxy-3′-methoxyacetophenone), a Known NADPH-Oxidase Inhibitor

GLUT1-mediated glycolysis supports GnRH-induced secretion of luteinizing hormone from female gonadotropes

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