Reverse‐mode <scp>NCX</scp> current in mouse airway smooth muscle: <scp><scp>N</scp></scp>a<sup>+</sup> and voltage dependence, contributions to <scp><scp>C</scp></scp>a<sup>2+</sup> influx and contraction, and altered expression in a model of allergen‐induced hyperresponsiveness

Rahman, Mozibur; Inman, Mark D.; Kiss, Lóránd; Janssen, Luke J.

doi:10.1111/j.1748-1716.2011.02401.x

Cited by 23 publications

(24 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A role of NCX in mitochondria cannot be ruled out, since pharmacological modulation could cause changes in calcium flux from this pool of calcium (Svichar et al 1999). There is evidence that KB-R7943 can enhance Cadependent potassium conductance (Rahman et al 2012), which could contribute to modulation of neurite degeneration, although this occurs with higher concentrations of the drug, e.g., 30 M (Rahman et al 2012). While not excluding a contribution via these other routes, our data point to a role of reverse NCX, triggered by activity of sodium channels, as a contributor to calcium overload in G856D-expressing DRG neurons.…”

Section: Discussionmentioning

confidence: 99%

Ca²⁺ toxicity due to reverse Na⁺/Ca²⁺ exchange contributes to degeneration of neurites of DRG neurons induced by a neuropathy-associated Nav1.7 mutation

Estacion

Vohra

Liu

et al. 2015

Journal of Neurophysiology

View full text Add to dashboard Cite

Gain-of-function missense mutations in voltage-gated sodium channel Nav1.7 have been linked to small-fiber neuropathy, which is characterized by burning pain, dysautonomia and a loss of intraepidermal nerve fibers. However, the mechanistic cascades linking Nav1.7 mutations to axonal degeneration are incompletely understood. The G856D mutation in Nav1.7 produces robust changes in channel biophysical properties, including hyperpolarized activation, depolarized inactivation, and enhanced ramp and persistent currents, which contribute to the hyperexcitability exhibited by neurons containing Nav1.8. We report here that cell bodies and neurites of dorsal root ganglion (DRG) neurons transfected with G856D display increased levels of intracellular Na(+) concentration ([Na(+)]) and intracellular [Ca(2+)] following stimulation with high [K(+)] compared with wild-type (WT) Nav1.7-expressing neurons. Blockade of reverse mode of the sodium/calcium exchanger (NCX) or of sodium channels attenuates [Ca(2+)] transients evoked by high [K(+)] in G856D-expressing DRG cell bodies and neurites. We also show that treatment of WT or G856D-expressing neurites with high [K(+)] or 2-deoxyglucose (2-DG) does not elicit degeneration of these neurites, but that high [K(+)] and 2-DG in combination evokes degeneration of G856D neurites but not WT neurites. Our results also demonstrate that 0 Ca(2+) or blockade of reverse mode of NCX protects G856D-expressing neurites from degeneration when exposed to high [K(+)] and 2-DG. These results point to [Na(+)] overload in DRG neurons expressing mutant G856D Nav1.7, which triggers reverse mode of NCX and contributes to Ca(2+) toxicity, and suggest subtype-specific blockade of Nav1.7 or inhibition of reverse NCX as strategies that might slow or prevent axon degeneration in small-fiber neuropathy.

show abstract

Section: Discussionmentioning

confidence: 99%

Ca²⁺ toxicity due to reverse Na⁺/Ca²⁺ exchange contributes to degeneration of neurites of DRG neurons induced by a neuropathy-associated Nav1.7 mutation

Estacion

Vohra

Liu

et al. 2015

Journal of Neurophysiology

View full text Add to dashboard Cite

show abstract

“…In ASM of humans without asthma, the reverse mode of NCX1 contributed to Ca 21 influx after histamine stimulation (46). Rahman and colleagues (47) recently suggested that the reverse mode of NCX1 altered Ca 21 mobility in mouse ASM. They also described increased gene expression of NCX1 in a chronic model with repeated HDM exposure that was not present in the acute model.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Alterations by DNA Methylation in House Dust Mite–Induced Airway Hyperresponsiveness

Shang

Das

Rabold

et al. 2013

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Asthma is one of the most prevalent chronic lung diseases, affecting 235 million individuals around the world, with its related morbidity and mortality increasing steadily over the last 20 years. Exposure to the environmental allergen, house dust mite (HDM), results in airway inflammation with a variable degree of airway obstruction. Although there has been much experimental work in the past using HDM challenge models to understand mechanistic details in allergic inflammation and airway hyperresponsiveness (AHR), there has been no study on reprogramming of lung or airways mediated through epigenetic mechanisms in response to an acute HDM exposure. Male mice, 6 weeks of age, were administrated HDM extracts or saline at Days 1, 14, and 21. Exposure of mice to HDM extracts caused significant airway inflammation and increased AHR. These HDMchallenged mice also exhibited a change in global DNA methylation as compared with saline-exposed (control) mice. Next, by employing methylation-sensitive restriction fingerprinting, we identified a set of genes, showing aberrant methylation status, associated with the HDM-induced AHR. These candidate genes are known to be involved in cAMP signaling (pde4 d), Akt-signaling (akt1 s1), ion transport (tm6 sf1, pom121l2, and slc8a3), and fatty acid metabolism (acsl3). Slc8a3 and acsl3 were down-regulated, whereas pde4 d, akt1 s1, tm6 sf1, and pom121l2 were up-regulated in the mice exposed to HDM. Hence, our results suggest that HDM exposure induces a series of aberrant methylated genes that are potentially important for the development of allergic AHR.Keywords: airway hyperresponsiveness; DNA methylation; epigenetics; house dust mite Asthma is one of the most prevalent chronic lung diseases, affecting 235 million individuals around the world (www.who.int). Individuals with asthma experience great difficulties in breathing and have reduced quality of life, with repeated visits to clinics or emergency rooms. It is well recognized that the development of asthma is related to a combination of genetic and environmental factors, but the precise mechanisms of pathogenesis in asthma are still unclear (1, 2). There are many triggers of asthmatic attacks; most of them are associated with environmental exposure to allergens. In the inner city environment, house dust mite (HDM) allergy is reported to be the most prevalent cause of allergic sensitization in individuals with asthma (3). Exposure to HDM results in airway inflammation with a variable degree of airway obstruction. In animal studies, chronic exposure of mice to HDM leads to significant airway inflammation, increased airway hyperresponsiveness (AHR), and remodeling of bronchi (4-6). Even though much work has been done in the past using this HDM model to probe the immunologic pathways, there is no study addressing the epigenetic basis of how this environmental allergen "reprograms" the airways, thereby predisposing the animals to asthma.Epigenetics provide a promising approach for improving our understanding of complex diseases like asth...

show abstract

“…Since changes in membrane potential are known to affect ASM Ca 2ϩ handling (39) and cytosolic Cl Ϫ concentration ([Cl Ϫ ]) has been implicated in attenuating sarcoplasmic Ca 2ϩ flux (21,23), we questioned whether activation of ␣5-subunit-containing GABA A receptors on ASM could modulate intracellular calcium concentration ([Ca 2ϩ ] i ) and mediate relaxation of intact ASM.…”

mentioning

confidence: 99%

Selective targeting of the α5-subunit of GABA_A receptors relaxes airway smooth muscle and inhibits cellular calcium handling

Gallos

Yocum

Siviski

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

Selective targeting of the ␣5-subunit of GABAA receptors relaxes airway smooth muscle and inhibits cellular calcium handling. Am J Physiol Lung Cell Mol Physiol 308: L931-L942, 2015. First published February 6, 2015 doi:10.1152/ajplung.00107.2014The clinical need for novel bronchodilators for the treatment of bronchoconstrictive diseases remains a major medical issue. Modulation of airway smooth muscle (ASM) chloride via GABA A receptor activation to achieve relaxation of precontracted ASM represents a potentially beneficial therapeutic option. Since human ASM GABAA receptors express only the ␣4-and ␣5-subunits, there is an opportunity to selectively target ASM GABAA receptors to improve drug efficacy and minimize side effects. Recently, a novel compound (R)-) with allosteric selectivity for ␣5-subunit containing GABAA receptors has become available. We questioned whether this novel GABAA ␣5-selective ligand relaxes ASM and affects intracellular calcium concentration ([Ca 2ϩ ]i) regulation. Immunohistochemical staining localized the GABAA ␣5-subunit to human ASM. The selective GABAA ␣5 ligand SH-053-2=F-R-CH3 relaxes precontracted intact ASM; increases GABA-activated chloride currents in human ASM cells in voltage-clamp electrophysiology studies; and attenuates bradykinin-induced increases in [Ca 2ϩ ]i, store-operated Ca 2ϩ entry, and methacholine-induced Ca 2ϩ oscillations in peripheral murine lung slices. In conclusion, selective subunit targeting of endogenous ␣5-subunit containing GABAA receptors on ASM may represent a novel therapeutic option to treat severe bronchospasm.GABAA ␣5-subunit; SH-053-2=F-R-CH3; airway relaxation DESPITE A PRESSING CLINICAL need for novel bronchodilators in the treatment of asthma and other bronchoconstrictive diseases, only three drug classes are currently in clinical use as acute bronchodilators in the United States (methylxanthines, anticholinergics, and ␤-adrenoceptor agonists) (6). An emerging novel pathway to achieve bronchodilation involves modulating airway smooth muscle (ASM) chloride conductance via GABA A receptors to achieve relaxation of human precontracted ASM (15). Although there is legitimate concern that widespread activation of all GABA A receptors may lead to undesirable side effects (sedation, hypnosis, etc.), we have shown that human ASM cells express a limited repertoire of GABA A receptor subunits, with the ␣4-and ␣5-subunits the only ␣-subunits expressed, thereby allowing for potential selective pharmacological tissue specific receptor targeting to minimize side effects (18,33). Inhaled delivery of these selective compounds may also serve to obviate concerns of systemic effects. Concern regarding nonselective GABA A receptor activation is not limited to the airway. GABA A receptor ligands active in the central nervous system (CNS) can have many effects including anxiolytic, sedative, hypnotic, amnesic, anticonvulsant, and muscle relaxant effects. This motivated a search for benzodiazepine (BDZ) ligands that discriminate among the ␣-subunits of ...

show abstract

Reverse‐mode NCX current in mouse airway smooth muscle: Na⁺ and voltage dependence, contributions to Ca²⁺ influx and contraction, and altered expression in a model of allergen‐induced hyperresponsiveness

Abstract: Reverse-mode NCX activity leads to a physiologically relevant increase in [Ca(2+) ] even under control conditions, and this may be exaggerated in allergen-induced AHR and asthma.

Cited by 23 publications

References 48 publications

Ca²⁺ toxicity due to reverse Na⁺/Ca²⁺ exchange contributes to degeneration of neurites of DRG neurons induced by a neuropathy-associated Nav1.7 mutation

Ca²⁺ toxicity due to reverse Na⁺/Ca²⁺ exchange contributes to degeneration of neurites of DRG neurons induced by a neuropathy-associated Nav1.7 mutation

Epigenetic Alterations by DNA Methylation in House Dust Mite–Induced Airway Hyperresponsiveness

Selective targeting of the α5-subunit of GABA_A receptors relaxes airway smooth muscle and inhibits cellular calcium handling

Contact Info

Product

Resources

About

Reverse‐mode NCX current in mouse airway smooth muscle: Na+ and voltage dependence, contributions to Ca2+ influx and contraction, and altered expression in a model of allergen‐induced hyperresponsiveness

Abstract: Reverse-mode NCX activity leads to a physiologically relevant increase in [Ca(2+) ] even under control conditions, and this may be exaggerated in allergen-induced AHR and asthma.

Cited by 23 publications

References 48 publications

Ca2+ toxicity due to reverse Na+/Ca2+ exchange contributes to degeneration of neurites of DRG neurons induced by a neuropathy-associated Nav1.7 mutation

Ca2+ toxicity due to reverse Na+/Ca2+ exchange contributes to degeneration of neurites of DRG neurons induced by a neuropathy-associated Nav1.7 mutation

Epigenetic Alterations by DNA Methylation in House Dust Mite–Induced Airway Hyperresponsiveness

Selective targeting of the α5-subunit of GABAA receptors relaxes airway smooth muscle and inhibits cellular calcium handling

Contact Info

Product

Resources

About

Reverse‐mode NCX current in mouse airway smooth muscle: Na⁺ and voltage dependence, contributions to Ca²⁺ influx and contraction, and altered expression in a model of allergen‐induced hyperresponsiveness

Ca²⁺ toxicity due to reverse Na⁺/Ca²⁺ exchange contributes to degeneration of neurites of DRG neurons induced by a neuropathy-associated Nav1.7 mutation

Ca²⁺ toxicity due to reverse Na⁺/Ca²⁺ exchange contributes to degeneration of neurites of DRG neurons induced by a neuropathy-associated Nav1.7 mutation

Selective targeting of the α5-subunit of GABA_A receptors relaxes airway smooth muscle and inhibits cellular calcium handling