Endophilin A2 regulates calcium-activated chloride channel activity via selective autophagy-mediated TMEM16A degradation

Liu, Canzhao; Li, Feiya; Lv, Xiao‐Fei; Ma, Ming; Li, Xiangyu; Lin, Caixia; Wang, Guan-Lei; Guan, Yong‐Yuan

doi:10.1038/s41401-019-0298-5

Cited by 11 publications

(12 citation statements)

References 40 publications

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“…Alternatively, it is conceivable that TMEM16A inhibitors that modulate ATP-induced intracellular calcium, could also interfere with other TMEM16A interacting partners to modulate channel activation and increase [Ca 2+ ]i. Thus, Liu et al (2020) found endophilin A2 regulated TMEM16A by autophagy-mediated degradation [48].…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Inhibition and Activation of the Ca2+ Activated Cl− Channel TMEM16A

Centeio

Cabrita

Benedetto

et al. 2020

IJMS

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TMEM16A is a Ca 2+ activated Cl − channel with important functions in airways, intestine, and other epithelial organs. Activation of TMEM16A is proposed as a therapy in cystic fibrosis (CF) to reinstall airway Cl − secretion and to enhance airway surface liquid (ASL). This CFTR-agnostic approach is thought to improve mucociliary clearance and lung function in CF. This could indeed improve ASL, however, mucus release and airway contraction may also be induced by activators of TMEM16A, particularly in inflamed airways of patients with asthma, COPD, or CF. Currently, both activators and inhibitors of TMEM16A are developed and examined in different types of tissues. Here we compare activation and inhibition of endogenous and overexpressed TMEM16A and analyze potential off-target effects. The three well-known blockers benzbromarone, niclosamide, and Ani9 inhibited both TMEM16A and ATP-induced Ca 2+ increase by variable degrees, depending on the cell type. Niclosamide, while blocking Ca 2+ activated TMEM16A, also induced a subtle but significant Ca 2+ store release and inhibited store-operated Ca 2+ influx. Niclosamide, benzbromarone and Ani9 also affected TMEM16F whole cell currents, indicating limited specificity for these inhibitors. The compounds Eact, cinnamaldehyde, and melittin, as well as the phosphatidylinositol diC8-PIP 2 are the reported activators of TMEM16A. However, the compounds were unable to activate endogenous TMEM16A in HT 29 colonic epithelial cells. In contrast, TMEM16A overexpressed in HEK293 cells was potently stimulated by these activators. We speculate that overexpressed TMEM16A might have a better accessibility to intracellular Ca 2+ , which causes spontaneous activity even at basal intracellular Ca 2+ concentrations. Small molecules may therefore potentiate pre-stimulated TMEM16A currents, but may otherwise fail to activate silent endogenous TMEM16A.

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Section: Discussionmentioning

confidence: 99%

Pharmacological Inhibition and Activation of the Ca2+ Activated Cl− Channel TMEM16A

Centeio

Cabrita

Benedetto

et al. 2020

IJMS

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“…Basilar artery smooth muscle cells (BASMCs) were isolated from rat and mice basilar arteries as we previously described [22]. Briefly, 4 weeks old male Sprague-Dawley rats, 5-8 weeks old Cftr +/+ and Cftr −/− mice were anesthetized with pentobarbital sodium (50 mg/kg, intraperitoneally).…”

Section: Cell Isolation and Culturementioning

confidence: 99%

CFTR deficiency aggravates Ang II induced vasoconstriction and hypertension by regulating Ca𝟐+ influx and RhoA/Rock pathway in VSMCs

Zhao¹,

Yuan²,

Pan³

et al. 2021

Front Biosci (Landmark Ed)

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Background: Cystic fibrosis transmembrane conductance regulator (CFTR) has been associated with vascular tone and blood pressure (BP), however, its role in the genesis of hypertension remains elusive. In the present study, we investigated the regulating effect of CFTR on angiotensin II (Ang II) -induced hypertension and defined the molecular role of CFTR in vasoconstriction. Results: We found that CFTR mRNA and protein expression were markedly down-regulated in the arteries from Ang II induced hypertensive animals. During the development of hypertension, BP of Cftr −/− mice was significantly higher than that of Cftr +/+ mice. Arteries from Cftr −/− mice or pre-incubated with CFTR specific inhibitor CFTR(inh)-172 exhibited a greater contractile response to Ang II. In vascular smooth muscle cells (VSMCs), the phosphorylation of myosin light chain (MLC), which is the core of VSMCs contraction, was negatively modulated by CFTR. Furthermore, intracellular Ca 2+ concentration ([Ca 2+ ] i ) rise in response to Ang II was negatively modulated by CFTR, while no alteration was observed in resting VSMCs. Ras homolog family member A/Rho-associated protein kinase (RhoA/Rock) mediated phosphorylation of myosin phosphatase target subunit 1 (MYPT1), a regulator of MLC phosphorylation, was negatively modulated by CFTR in both resting and Ang II-stimulated VSMCs. Conclusions: This study demonstrates that CFTR is a negative regulator of vasoconstriction and hypertension, and the underlying mechanism contains two possible pathways: (1) in resting VSMCs, CFTR altered MLC phosphorylation through RhoA/Rock pathway; (2) in Ang II stimulated VSMCs, the regulating effect was mediated by both Ca 2+ influx and RhoA/Rock mediated pathway.

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“…The LRRC8A‐FLAG plasmid was a gift from Dr. Zhaozhu Qiu (Howard Hughes Medical Institute, USA). Adenovirus transduction was performed according to the protocol as previously described 27 . BASMCs were transduced with adenovirus when the cells reached 50% confluence.…”

Section: Methodsmentioning

confidence: 99%

“…Adenovirus transduction was performed according to the protocol as previously described. 27 BASMCs were transduced with adenovirus when the cells reached 50% confluence.…”

Section: Methodsmentioning

confidence: 99%

LRRC8A is essential for volume‐regulated anion channel in smooth muscle cells contributing to cerebrovascular remodeling during hypertension

Huang

et al. 2021

Cell Proliferation

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Objectives Recent studies revealed LRRC8A to be an essential component of volume‐regulated anion channel (VRAC), which regulates cellular volume homeostasis. However, evidence for the contribution of LRRC8A‐dependent VRAC activity in vascular smooth muscle cells (VSMCs) is still lacking, and the relevant functional role of LRRC8A in VSMCs remains unknown. The primary goal of this study was to elucidate the role of LRRC8A in VRAC activity in VSMCs and the functional role of LRRC8A in cerebrovascular remodeling during hypertension. Materials and Methods siRNA‐mediated knockdown and adenovirus‐mediated overexpression of LRRC8A were used to elucidate the electrophysiological properties of LRRC8A in basilar smooth muscle cells (BASMCs). A smooth muscle–specific overexpressing transgenic mouse model was used to investigate the functional role of LRRC8A in cerebrovascular remodeling. Results LRRC8A is essential for volume‐regulated chloride current (ICl, Vol) in BASMCs. Overexpression of LRRC8A induced a voltage‐dependent Cl− current independently of hypotonic stimulation. LRRC8A regulated BASMCs proliferation through activation of WNK1/PI3K‐p85/AKT axis. Smooth muscle‐specific upregulation of LRRC8A aggravated Angiotensin II‐induced cerebrovascular remodeling in mice. Conclusions LRRC8A is an essential component of VRAC and is required for cell volume homeostasis during osmotic challenge in BASMCs. Smooth muscle specific overexpression of LRRC8A increases BASMCs proliferation and substantially aggravates basilar artery remodeling, revealing a potential therapeutic target for vascular remodeling in hypertension.

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Endophilin A2 regulates calcium-activated chloride channel activity via selective autophagy-mediated TMEM16A degradation

Cited by 11 publications

References 40 publications

Pharmacological Inhibition and Activation of the Ca2+ Activated Cl− Channel TMEM16A

Pharmacological Inhibition and Activation of the Ca2+ Activated Cl− Channel TMEM16A

CFTR deficiency aggravates Ang II induced vasoconstriction and hypertension by regulating Ca𝟐+ influx and RhoA/Rock pathway in VSMCs

LRRC8A is essential for volume‐regulated anion channel in smooth muscle cells contributing to cerebrovascular remodeling during hypertension

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