<scp>LRRC8A</scp> anion channels modulate vascular reactivity via association with myosin phosphatase rho interacting protein

Choi, Hyehun; Miller, Michael R.; Nguyen, Hong‐Ngan; Rohrbough, Jeffrey; Koch, Stephen R.; Boatwright, Naoko; Yarboro, Michael T.; Sah, Rajan; Reese, Jeff; Stark, Ryan J.; Lamb, Fred S.

doi:10.1096/fj.202300561r

Cited by 4 publications

(12 citation statements)

References 59 publications

(125 reference statements)

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“…To determine the contribution of LRRC8A to TNF-α signaling in intact blood vessels, VSMC-specific LRRC8A knockout mice were created. 118 Mesenteric vessels from knockout mice were protected from the adverse effects of a 48-hour exposure to TNF-α; enhanced constriction and impaired vasodilation were prevented. Surprisingly, independent of cytokine exposure, knockout vessels displayed markedly enhanced vasodilation in response to multiple stimuli.…”

Section: Defining a Multiprotein O 2 •− Signaling Complex In Vsmcsmentioning

confidence: 99%

“…Consistent with these concepts, TNF-α treatment of airway smooth muscle cells enhanced contractility via a combination of enhanced Ca 2+ sensitivity and actin polymerization. 130 A multiprotein complex may allow O 2 •− produced by Nox1 to regulate contractility 103,118 (Figure 3). Association of Nox1/LRRC8A with MPRIP brings the source of O 2…”

Section: Figure 1 Loss Of Ecsod Promotes Apoptosis Signaling-related ...mentioning

confidence: 99%

“…This was observed in cultured VSMCs from LRRC8A knockout mouse mesenteric arteries exposed to TNF-α (Figure 4). MPRIP is oxidized by TNF-α in an LRRC8A-dependent manner 118 and complex assembly may, therefore, be redox regulated. This may be important because association of MPRIP with MYPT1 enhances LRRC8A localizes to the plasma membrane and the surface of intracellular vesicles (see Reference [124] for details).…”

Section: Figure 1 Loss Of Ecsod Promotes Apoptosis Signaling-related ...mentioning

confidence: 99%

“…Knockdown of ecSOD was very effective (>90%). 118 B , Proposed mechanism of thioredoxin oxidation in response to TNF-α. Nox1 associates with tumor necrosis factor receptor type 1 (TNFR1) via mutual binding to riboflavin kinase 105,106 and also binds LRRC8 (leucine-rich repeat containing 8) volume-regulated anion channels (VRACs).…”

Section: Can O2•− Cross Membranes?mentioning

confidence: 99%

“…107 LRRC8A was immunoprecipitated and mass spectroscopy was used to identify proteins that were pulled down in wild type, but not knockout VSMCs. 118 Analysis of the identified proteins pointed to actin filament regulation. Among them, MPRIP (myosin phosphatase Rho-interacting protein) is a scaffolding protein that binds RhoA, MYPT1, and actin, 121 and is essential for MLCP regulation of the actin cytoskeleton.…”

Section: Defining a Multiprotein O2•− Signaling Complex In Vsmcsmentioning

confidence: 99%

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Vascular Inflammation and Smooth Muscle Contractility: The Role of Nox1-Derived Superoxide and LRRC8 Anion Channels

Lamb,

Choi,

Miller

et al. 2024

Hypertension

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Vascular inflammation underlies the development of hypertension, and the mechanisms by which it increases blood pressure remain the topic of intense investigation. Proinflammatory factors including glucose, salt, vasoconstrictors, cytokines, wall stress, and growth factors enhance contractility and impair relaxation of vascular smooth muscle cells. These pathways share a dependence upon redox signaling, and excessive activation promotes oxidative stress that promotes vascular aging. vascular smooth muscle cell phenotypic switching and migration into the intima contribute to atherosclerosis, while hypercontractility increases systemic vascular resistance and vasospasm that can trigger ischemia. Here, we briefly review factors that drive the initiation and progression of this vasculopathy in vascular smooth muscle cells. Emphasis is placed on the contribution of reactive oxygen species generated by the Nox1 NADPH oxidase which produces extracellular superoxide (O 2 •− ). The mechanisms of O 2 •− signaling remain poorly defined, but recent evidence demonstrates physical association of Nox1 with leucine-rich repeat containing 8 family volume-sensitive anion channels . These may provide a pathway for influx of O 2 •− to the cytoplasm, creating an oxidized cytoplasmic nanodomain where redox-based signals can affect both cytoskeletal structure and vasomotor function. Understanding the mechanistic links between inflammation, O 2 •− and vascular smooth muscle cell contractility may facilitate targeting of anti-inflammatory therapy in hypertension.

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Section: Defining a Multiprotein O 2 •− Signaling Complex In Vsmcsmentioning

confidence: 99%

Section: Figure 1 Loss Of Ecsod Promotes Apoptosis Signaling-related ...mentioning

confidence: 99%

Section: Figure 1 Loss Of Ecsod Promotes Apoptosis Signaling-related ...mentioning

confidence: 99%

Section: Can O2•− Cross Membranes?mentioning

confidence: 99%

Section: Defining a Multiprotein O2•− Signaling Complex In Vsmcsmentioning

confidence: 99%

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Vascular Inflammation and Smooth Muscle Contractility: The Role of Nox1-Derived Superoxide and LRRC8 Anion Channels

Lamb,

Choi,

Miller

et al. 2024

Hypertension

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Extracellular SOD modulates canonical TNFα signaling and α5β1 integrin transactivation in vascular smooth muscle cells

Choi,

Miller,

Nguyen

et al. 2023

Free Radical Biology and Medicine

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Recent advances in the structure, function and regulation of the volume‐regulated anion channels and their role in immunity

Yanushkevich,

Zieminska,

Gonzalez

et al. 2024

The Journal of Physiology

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Volume‐regulated anion channels (VRACs) are heteromeric complexes formed by proteins of the leucine‐rich repeat‐containing 8 (LRRC8) family. LRRC8A (also known as SWELL1) is the core subunit required for VRAC function, and it must combine with one or more of the other paralogues (i.e. LRRC8B–E) to form functional heteromeric channels. VRACs were discovered in T lymphocytes over 35 years ago and are found in virtually all vertebrate cells. Initially, these anion channels were characterized for their role in Cl− efflux during the regulatory volume decrease process triggered when cells are subjected to hypotonic challenges. However, substantial evidence suggests that VRACs also transport small molecules under isotonic conditions. These findings have expanded the research on VRACs to explore their functions beyond volume regulation. In innate immune cells, VRACs promote inflammation by modulating the transport of immunomodulatory cyclic dinucleotides, itaconate and ATP. In adaptive immune cells, VRACs suppress their function by taking up cyclic dinucleotides to activate the STING signalling pathway. In this review, we summarize the current understanding of LRRC8 proteins in immunity and discuss recent progress in their structure, function, regulation and mechanisms for channel activation and gating. Finally, we also examine potential immunotherapeutic applications of VRAC modulation. image

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LRRC8A anion channels modulate vascular reactivity via association with myosin phosphatase rho interacting protein

Cited by 4 publications

References 59 publications

Vascular Inflammation and Smooth Muscle Contractility: The Role of Nox1-Derived Superoxide and LRRC8 Anion Channels

Vascular Inflammation and Smooth Muscle Contractility: The Role of Nox1-Derived Superoxide and LRRC8 Anion Channels

Extracellular SOD modulates canonical TNFα signaling and α5β1 integrin transactivation in vascular smooth muscle cells

Recent advances in the structure, function and regulation of the volume‐regulated anion channels and their role in immunity

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