Impairment of Store-Operated Ca
            <sup>2+</sup>
            Entry in TRPC4
            <sup>−/−</sup>
            Mice Interferes With Increase in Lung Microvascular Permeability

Tiruppathì, Chinnaswamy; Freichel, Marc; Vogel, Stephen M.; Paria, Biman C.; Mehta, Dolly; Flockerzi, Veit; Malik, Asrar B.

doi:10.1161/01.res.0000023391.40106.a8

Cited by 345 publications

(309 citation statements)

References 21 publications

(48 reference statements)

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“…We chose 4 kHz because this frequency exhibits the greatest response seen in a multifrequency spectrum for our monolayers in comparisons of early and mature monolayers. This frequency also permits comparison of our findings to a considerable number of ECIS-related publications dealing with endothelial biology where the same frequency is employed (41,42). After irradiation, we observed changes in the transmonolayer impedance of HCAEC monolayers.…”

Section: Discussionmentioning

confidence: 55%

Low-Dose Ionizing Radiation Stimulates Transcription and Production of Endothelin by Human Vein Endothelial Cells

et al. 2007

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Section: Discussionmentioning

confidence: 55%

Low-Dose Ionizing Radiation Stimulates Transcription and Production of Endothelin by Human Vein Endothelial Cells

et al. 2007

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“…Human ␣-thrombin was obtained from Enzyme Research Laboratories (South Bend, IN). Protease-activated receptor-1 (PAR-1)-activating peptide (TFFLRNPNDK-NH 2 ) was synthesized as a C-terminal amide (16). Fura-2AM was purchased from Invitrogen.…”

Section: Methodsmentioning

confidence: 99%

“…Mouse (C57BL6) lung endothelial cells (mLECs) were isolated and cultured as described previously (16,17). HLMVECs were grown in EGM-2MV supplemented with 15% FBS, and mLECs were grown in EGM-2 supplemented with 5% FBS (growth media from Lonza).…”

Section: Methodsmentioning

confidence: 99%

Store-operated Ca2+ Entry (SOCE) Induced by Protease-activated Receptor-1 Mediates STIM1 Protein Phosphorylation to Inhibit SOCE in Endothelial Cells through AMP-activated Protein Kinase and p38β Mitogen-activated Protein Kinase

Sundivakkam

Natarajan

Malik

et al. 2013

Journal of Biological Chemistry

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The Ca2+ sensor STIM1 is crucial for activation of store-operated Ca2+ entry (SOCE) through transient receptor potential canonical and Orai channels. STIM1 phosphorylation serves as an “off switch” for SOCE. However, the signaling pathway for STIM1 phosphorylation is unknown. Here, we show that SOCE activates AMP-activated protein kinase (AMPK); its effector p38β mitogen-activated protein kinase (p38β MAPK) phosphorylates STIM1, thus inhibiting SOCE in human lung microvascular endothelial cells. Activation of AMPK using 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) resulted in STIM1 phosphorylation on serine residues and prevented protease-activated receptor-1 (PAR-1)-induced Ca2+ entry. Furthermore, AICAR pretreatment blocked PAR-1-induced increase in the permeability of mouse lung microvessels. Activation of SOCE with thrombin caused phosphorylation of isoform α1 but not α2 of the AMPK catalytic subunit. Moreover, knockdown of AMPKα1 augmented SOCE induced by thrombin. Interestingly, SB203580, a selective inhibitor of p38 MAPK, blocked STIM1 phosphorylation and led to sustained STIM1-puncta formation and Ca2+ entry. Of the three p38 MAPK isoforms expressed in endothelial cells, p38β knockdown prevented PAR-1-mediated STIM1 phosphorylation and potentiated SOCE. In addition, inhibition of the SOCE downstream target CaM kinase kinase β (CaMKKβ) or knockdown of AMPKα1 suppressed PAR-1-mediated phosphorylation of p38β and hence STIM1. Thus, our findings demonstrate that SOCE activates CaMKKβ-AMPKα1-p38β MAPK signaling to phosphorylate STIM1, thereby suppressing endothelial SOCE and permeability responses.

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“…In endothelial cell lines, several studies have demonstrated that TRPC1 [36] and TRPC4 [37,38] participate to SOCE. On the contrary, a recent study showed in primary human umbilical vein endothelial cells (HUVECs) that SOCE is mediated almost exclusively by the STIM1/Orai1 machinery [39].…”

Section: Sensementioning

confidence: 99%

Thapsigargin activates Ca2+ entry both by store-dependent, STIM1/Orai1-mediated, and store-independent, TRPC3/PLC/PKC-mediated pathways in human endothelial cells

et al. 2011

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a b s t r a c tThe ER Ca 2+ sensor STIM1 and the Ca 2+ channel Orai1 are key players in store-operated Ca 2+ entry (SOCE). In addition, channels from the TRPC family were also shown to be engaged during SOCE, while their precise implication remains controversial. In this study, we investigated the molecular players involved in SOCE triggered by the SERCA pump inhibitor thapsigargin in an endothelial cell line, the EA.hy926. siRNA directed against STIM1 or Orai1 reduced Ca 2+ entry by about 50-60%, showing that a large part of the entry is independent from these proteins. Blocking the PLC or the PKC pathway completely abolished thapsigargin-induced Ca 2+ entry in cells depleted from STIM1 and/or Orai1. The phorbol ester PMA or the DAG analog OAG restored the Ca 2+ entry inhibited by PLC blockers, showing an involvement of PLC/PKC pathway in SOCE. Using pharmacological inhibitors or siRNA revealed that the PKCeta is required for Ca 2+ entry, and pharmacological inhibition of the tyrosine kinase Src also reduced Ca 2+ entry. TRPC3 silencing diminished the entry by 45%, while the double STIM1/TRPC3 invalidation reduced Ca 2+ entry by more than 85%. Hence, in EA.hy926 cells, TG-induced Ca 2+ entry results from the activation of the STIM1/Orai1 machinery, and from the activation of TRPC3.

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Impairment of Store-Operated Ca ²⁺ Entry in TRPC4 ^−/− Mice Interferes With Increase in Lung Microvascular Permeability

Cited by 345 publications

References 21 publications

Low-Dose Ionizing Radiation Stimulates Transcription and Production of Endothelin by Human Vein Endothelial Cells

Low-Dose Ionizing Radiation Stimulates Transcription and Production of Endothelin by Human Vein Endothelial Cells

Store-operated Ca2+ Entry (SOCE) Induced by Protease-activated Receptor-1 Mediates STIM1 Protein Phosphorylation to Inhibit SOCE in Endothelial Cells through AMP-activated Protein Kinase and p38β Mitogen-activated Protein Kinase

Thapsigargin activates Ca2+ entry both by store-dependent, STIM1/Orai1-mediated, and store-independent, TRPC3/PLC/PKC-mediated pathways in human endothelial cells

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Impairment of Store-Operated Ca 2+ Entry in TRPC4 −/− Mice Interferes With Increase in Lung Microvascular Permeability

Cited by 345 publications

References 21 publications

Low-Dose Ionizing Radiation Stimulates Transcription and Production of Endothelin by Human Vein Endothelial Cells

Low-Dose Ionizing Radiation Stimulates Transcription and Production of Endothelin by Human Vein Endothelial Cells

Store-operated Ca2+ Entry (SOCE) Induced by Protease-activated Receptor-1 Mediates STIM1 Protein Phosphorylation to Inhibit SOCE in Endothelial Cells through AMP-activated Protein Kinase and p38β Mitogen-activated Protein Kinase

Thapsigargin activates Ca2+ entry both by store-dependent, STIM1/Orai1-mediated, and store-independent, TRPC3/PLC/PKC-mediated pathways in human endothelial cells

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Impairment of Store-Operated Ca ²⁺ Entry in TRPC4 ^−/− Mice Interferes With Increase in Lung Microvascular Permeability