PICK1/calcineurin suppress ASIC1-mediated Ca<sup>2+</sup> entry in rat pulmonary arterial smooth muscle cells

Herbert, Lindsay M.; Nitta, Carlos H.; Yellowhair, Tracylyn R.; Browning, Carly; Bosc, Laura V. González; Resta, Thomas C.; Jernigan, Nikki L.

doi:10.1152/ajpcell.00091.2015

Cited by 15 publications

(24 citation statements)

References 54 publications

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“…Indeed, similar to basal [Ca 2ϩ ] i levels, we also found that SOCE was largely augmented in PASMC from ASIC2 Ϫ/Ϫ mice. Consistent with our previous studies (22,23,25,27,28), this enhanced SOCE response is mediated largely by ASIC1. In addition, pretreatment with PcTX1 abolished the elevation in basal [Ca 2ϩ ] i levels in PASMC from ASIC2 Ϫ/Ϫ mice.…”

Section: Discussionsupporting

confidence: 92%

Loss of acid-sensing ion channel 2 enhances pulmonary vascular resistance and hypoxic pulmonary hypertension

Detweiler

Herbert

Garcia

et al. 2019

Journal of Applied Physiology

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Acid-sensing ion channels (ASICs) are voltage-insensitive cation channels that contribute to cellular excitability. We previously reported that ASIC1 in pulmonary artery smooth muscle cells (PASMC) contribute to pulmonary vasoreactivity and vascular remodeling during the development of chronic hypoxia (CH)-induced pulmonary hypertension. However, the roles of ASIC2 and ASIC3 in regulation of pulmonary vasoreactivity and the development of CH-induced pulmonary hypertension are unknown. We tested the hypothesis that ASIC2 and ASIC3 contribute to increased pulmonary vasoreactivity and development of CH-induced pulmonary hypertension using ASIC2- and ASIC3-knockout (−/−) mice. In contrast to this hypothesis, we found that ASIC2−/− mice exhibit enhanced CH-induced pulmonary hypertension compared with WT and ASIC3−/− mice. This response was not associated with a change in ventilatory sensitivity or systemic cardiovascular function but was instead associated with direct changes in pulmonary vascular reactivity and pulmonary arterial morphology in ASIC2−/− mice. This increase in reactivity correlated with enhanced pulmonary arterial basal tone, elevated basal PASMC [Ca2+] and store-operated calcium entry (SOCE) in PASMC from ASIC2−/− mice. This increase in PASMC [Ca2+] and vasoreactivity was dependent on ASIC1-mediated Ca2+ influx but was not contingent upon an increase in ASIC1 mRNA or protein expression in PASMC from ASIC2−/− mice. Together, the results from this study demonstrate an important role for ASIC2 to regulate pulmonary vascular reactivity and for ASIC2 to modulate the development of CH-induced pulmonary hypertension. These data further suggest that loss of ASIC2 enhances the contribution of ASIC1 to overall pulmonary vascular reactivity. NEW & NOTEWORTHY This study demonstrates that loss of ASIC2 leads to increased baseline pulmonary vascular resistance, enhanced responses to a variety of vasoconstrictor stimuli, and greater development of hypoxic pulmonary hypertension. Furthermore, these results suggest that loss of ASIC2 enhances the contribution of ASIC1 to pulmonary vascular reactivity.

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Section: Discussionsupporting

confidence: 92%

Loss of acid-sensing ion channel 2 enhances pulmonary vascular resistance and hypoxic pulmonary hypertension

Detweiler

Herbert

Garcia

et al. 2019

Journal of Applied Physiology

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“…The direct interaction between Eag1 and MKRN1 long isoform, but not the short isoform, in HEK293T cells was further validated by the in situ proximity ligation assay (PLA) ( Fig. 1 C ), which detects immunofluorescence signals generated from a pair of oligonucleotide-linked antibodies recognizing two proteins that are in close proximity (<40 nm) ( 25 , 26 , 27 ). Together these observations indicate that Eag1 interacts primarily with the C-terminal region of the long isoform of MKRN1.…”

Section: Resultsmentioning

confidence: 95%

Identification of MKRN1 as a second E3 ligase for Eag1 potassium channels reveals regulation via differential degradation

Fang

Hsu

et al. 2021

Journal of Biological Chemistry

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Mutations in the human gene encoding the neuron-specific Eag1 voltage-gated K + channel are associated with neurodevelopmental diseases, indicating an important role of Eag1 during brain development. A disease-causing Eag1 mutation is linked to decreased protein stability that involves enhanced protein degradation by the E3 ubiquitin ligase cullin 7 (CUL7). The general mechanisms governing protein homeostasis of plasma membrane- and endoplasmic reticulum (ER)-localized Eag1 K + channels, however, remain unclear. By using yeast two-hybrid screening, we identified another E3 ubiquitin ligase, makorin ring finger protein 1 (MKRN1), as a novel binding partner primarily interacting with the carboxyl-terminal region of Eag1. MKRN1 mainly interacts with ER-localized immature core-glycosylated, as well as nascent nonglycosylated, Eag1 proteins. MKRN1 promotes polyubiquitination and ER-associated proteasomal degradation of immature Eag1 proteins. Although both CUL7 and MKRN1 contribute to ER quality control of immature core-glycosylated Eag1 proteins, MKRN1, but not CUL7, associates with and promotes degradation of nascent, nonglycosylated Eag1 proteins at the ER. In direct contrast to the role of CUL7 in regulating both ER and peripheral quality controls of Eag1, MKRN1 is exclusively responsible for the early stage of Eag1 maturation at the ER. We further demonstrated that both CUL7 and MKRN1 contribute to protein quality control of additional disease-causing Eag1 mutants associated with defective protein homeostasis. Our data suggest that the presence of this dual ubiquitination system differentially maintains Eag1 protein homeostasis and may ensure efficient removal of disease-associated misfolded Eag1 mutant channels.

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“…increased intracellular Ca 2+ ([Ca 2+ ]i) level can increase calpain activity [14]. Calcineurin is a protein phosphatase known as serine/threonine phosphatase and can be activated physiologically by Ca 2+ /calmodulin during the differentiation of skeletal muscles and the development of osteoclasts in bone [15]. Our present study showed that extracellu-…”

Section: Discussionmentioning

confidence: 53%

Effect of Activation of the Ca<sup>2+</sup>-Permeable Acid-Sensing Ion Channel 1a on Acid-Induced Vascular Endothelial Cell Injury of Henoch-Schönlein Purpura Children

Peng¹,

Yuan²,

Yan³

et al. 2016

OJPed

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Acidosis in local environment plays a critical role in cell injury. One key mediator of acidosis-induced cell injury is the acid-sensing ion channels (ASICs), particularly ASIC1a. Herein, we investigated the role of ASIC1a in acid-induced vascular endothelial cell injury of Henoch-Schönlein purpura (HSP) children. Acid-induced ASIC1a, Calpain and Calcineurin expression in vascular endothelial cells pretreated with IgA1 isolated from HSP were detected by real time quantitative polymerase chain reaction and western blot methods, respectively. Cell cytotoxicity was measured by interleukin-8 and nitric oxide production with ELISA. The results showed acid-induced ASIC1a, Calpain and Calcineurin expression in cells increased, especially at PH6.5. The cytotoxicity of vascular endothelial cells was increased by extracellular acidosis. Moreover non-specific or specific blockers of ASIC1a, Amiloride and PcTX-1 could remarkably decrease these parameters. These findings show that increased [Ca 2+ ]i, mediated via ASIC1a, might contribute to acid-induced vascular endothelial cell injury of HSP.

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PICK1/calcineurin suppress ASIC1-mediated Ca²⁺ entry in rat pulmonary arterial smooth muscle cells

Cited by 15 publications

References 54 publications

Loss of acid-sensing ion channel 2 enhances pulmonary vascular resistance and hypoxic pulmonary hypertension

Loss of acid-sensing ion channel 2 enhances pulmonary vascular resistance and hypoxic pulmonary hypertension

Identification of MKRN1 as a second E3 ligase for Eag1 potassium channels reveals regulation via differential degradation

Effect of Activation of the Ca<sup>2+</sup>-Permeable Acid-Sensing Ion Channel 1a on Acid-Induced Vascular Endothelial Cell Injury of Henoch-Schönlein Purpura Children

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PICK1/calcineurin suppress ASIC1-mediated Ca2+ entry in rat pulmonary arterial smooth muscle cells

Cited by 15 publications

References 54 publications

Loss of acid-sensing ion channel 2 enhances pulmonary vascular resistance and hypoxic pulmonary hypertension

Loss of acid-sensing ion channel 2 enhances pulmonary vascular resistance and hypoxic pulmonary hypertension

Identification of MKRN1 as a second E3 ligase for Eag1 potassium channels reveals regulation via differential degradation

Effect of Activation of the Ca&lt;sup&gt;2+&lt;/sup&gt;-Permeable Acid-Sensing Ion Channel 1a on Acid-Induced Vascular Endothelial Cell Injury of Henoch-Sch&#246;nlein Purpura Children

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PICK1/calcineurin suppress ASIC1-mediated Ca²⁺ entry in rat pulmonary arterial smooth muscle cells

Effect of Activation of the Ca<sup>2+</sup>-Permeable Acid-Sensing Ion Channel 1a on Acid-Induced Vascular Endothelial Cell Injury of Henoch-Schönlein Purpura Children