The Lbc Rho Guanine Nucleotide Exchange Factor/α-Catulin Axis Functions in Serotonin-induced Vascular Smooth Muscle Cell Mitogenesis and RhoA/ROCK Activation*

Bear, Michael; Li, Min; Liu, Yinglin; Giel–Moloney, Maryann; Fanburg, Barry L.; Toksoz, Deniz

doi:10.1074/jbc.m109.062513

Cited by 20 publications

(26 citation statements)

References 48 publications

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“…S2). A parallel study revealed that α-catulin bridges 5-hydroxytryptamine-2 receptor Gαq/11 coupling to activation of the Lbc-RhoGEF/RhoA/ROCK pathway in pulmonary artery smooth muscle cells (22). Thus, these combined results implicate α-catulin as a unique regulator of membrane receptor function, and herein we provide a detailed molecular mechanism by which α-catulin links these membrane signaling proteins to the DAPC through α-DB1.…”

Section: Discussionmentioning

confidence: 77%

“…Because the α 1D -AR is the only α 1 -AR subtype that interacts with the DAPC/α-catulin complex (5,10), the findings of this study may provide a mechanistic explanation to the mystery of GPCR supersensitivity, a physiological process observed in hypertension and benign prostatic hypertrophy (12). Additionally, it is interesting to note that all identified α-catulin binding proteins are modulated by Gαq/11 signaling (22,29). Thus, we propose that α-catulin is a key component of Gαq/11 signaling complexes, where it functions to recruit activator and effector proteins in close proximity to each other.…”

Section: Discussionmentioning

confidence: 92%

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α-Dystrobrevin-1 recruits α-catulin to the α _1D -adrenergic receptor/dystrophin-associated protein complex signalosome

Lyssand¹,

Whiting

Lee³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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α 1D -Adrenergic receptors (ARs) are key regulators of cardiovascular system function that increase blood pressure and promote vascular remodeling. Unfortunately, little information exists about the signaling pathways used by this important G protein-coupled receptor (GPCR). We recently discovered that α 1D -ARs form a “signalosome” with multiple members of the dystrophin-associated protein complex (DAPC) to become functionally expressed at the plasma membrane and bind ligands. However, the molecular mechanism by which the DAPC imparts functionality to the α 1D -AR signalosome remains a mystery. To test the hypothesis that previously unidentified molecules are recruited to the α 1D -AR signalosome, we performed an extensive proteomic analysis on each member of the DAPC. Bioinformatic analysis of our proteomic data sets detected a common interacting protein of relatively unknown function, α-catulin. Coimmunoprecipitation and blot overlay assays indicate that α-catulin is directly recruited to the α 1D -AR signalosome by the C-terminal domain of α-dystrobrevin-1 and not the closely related splice variant α-dystrobrevin-2. Proteomic and biochemical analysis revealed that α-catulin supersensitizes α 1D -AR functional responses by recruiting effector molecules to the signalosome. Taken together, our study implicates α-catulin as a unique regulator of GPCR signaling and represents a unique expansion of the intricate and continually evolving array of GPCR signaling networks.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 92%

α-Dystrobrevin-1 recruits α-catulin to the α _1D -adrenergic receptor/dystrophin-associated protein complex signalosome

Lyssand¹,

Whiting

Lee³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Cells were transfected with a plasmid containing a MR-response element reporter driving expression of the luciferase gene or control reporter containing an estrogen receptor response element, as previously described (22). After 24 h of serum starvation, indicated concentrations of vehicle, ligand, and inhibitor or its vehicle were then added for 18 h. Cells were lysed, and luciferase activity was determined in triplicate, as described (3,14).…”

Section: Methodsmentioning

confidence: 99%

Mineralocorticoid receptor antagonism attenuates experimental pulmonary hypertension

Preston

Sagliani

Warburton

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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We hypothesized that MR contributes to pulmonary vascular and right ventricular (RV) remodeling of pulmonary hypertension (PH). We evaluated the efficacy of MR antagonism by spironolactone in two experimental PH models; mouse chronic hypoxia-induced PH (prevention model) and rat monocrotaline-induced PH (prevention and treatment models). Last, the biological function of the MR was analyzed in cultured distal pulmonary artery smooth muscle cells (PASMCs). In hypoxic PH mice, spironolactone attenuated the increase in RV systolic pressure, pulmonary arterial muscularization, and RV fibrosis. In rat monocrotaline-induced PH (prevention arm), spironolactone attenuated pulmonary vascular resistance and pulmonary vascular remodeling. In the established disease (treatment arm), spironolactone decreased RV systolic pressure and pulmonary vascular resistance with no significant effect on histological measures of pulmonary vascular remodeling, or RV fibrosis. Spironolactone decreased RV cardiomyocyte size modestly with no significant effect on RV mass, systemic blood pressure, cardiac output, or body weight, suggesting a predominantly local pulmonary vascular effect. In distal PASMCs, MR was expressed and localized diffusely. Treatment with the MR agonist aldosterone, hypoxia, or plateletderived growth factor promoted MR translocation to the nucleus, activated MR transcriptional function, and stimulated PASMC proliferation, while spironolactone blocked these effects. In summary, MR is active in distal PASMCs, and its antagonism prevents PASMC proliferation and attenuates experimental PH. These data suggest that MR is involved in the pathogenesis of PH via effects on PASMCs and that MR antagonism may represent a novel therapeutic target for this disease.aldosterone; hypoxia; monocrotaline; pulmonary vascular remodeling; spironolactone PULMONARY ARTERIAL HYPERTENSION (PAH) is a progressive, fatal disease. In its idiopathic form, mortality is 30 -50% at five years, even with recent advances in available therapies. In its secondary forms, pulmonary hypertension (PH) contributes significantly to the morbidity and mortality of chronic lung and heart diseases. The pathological changes include medial thickening of the pulmonary vasculature due to smooth muscle cell (SMC) hyperplasia and hypertrophy (12

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“…ese agents include fen�uramine, L-tryptophan, cocaine, monocrotaline, and amphetamines, which are all thought to act via elevated serotonin to initiate cases of PAH [155][156][157][158][159][160][161]. Oxidative stress responses are involved here [148,162] as are increased levels of in�ammatory cytokines [163].…”

Section: Principlementioning

confidence: 99%

“…Oxidative stress responses are involved here [148,162] as are increased levels of in�ammatory cytokines [163]. Serotonin is thought to act, at least in part, by raising levels of a regulatory peptide known as RhoA [155,156,161]. RhoA is also thought to have roles in several other types of PAH cases including cases involving bleomycin, hypoxia, and endotoxin exposure It is important, therefore, to determine whether RhoA levels may be elevated in response to NO/ONOO − cycle elements and also whether it, in turn, may elevate NO/ONOO − cycle elements.…”

Section: Principlementioning

confidence: 99%

Pulmonary Hypertension Is a Probable NO/ONOO⁻Cycle Disease: A Review

Pall

2013

ISRN Hypertension

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e NO/ONOO − cycle is a primarily local biochemical/physiological vicious cycle that appears to cause a series of chronic in�ammatory diseases. is paper focuses on whether the cycle causes pulmonary arterial hypertension (PAH) when located in the pulmonary arteries. e cycle involves 12 elements, including superoxide, peroxynitrite (ONOO − ), nitric oxide (NO), oxidative stress, NF-B, in�ammatory cytokines, iNOS, mitochondrial dysfunction, intracellular calcium, tetrahydrobiopterin depletion, NMDA activity, and TRP receptor activity. 10 of the 12 are elevated in PAH (NMDA?, NO?) and 11 have documented causal roles in PAH. Each stressor that initiates cases of PAH acts to raise cycle elements, and may, therefore, initiate the cycle in this way. PAH involves a primarily local mechanism as required by the cycle and the symptoms and signs of PAH are generated by elements of the cycle. Endothelin-1, which acts as a causal factor in PAH, acts as part of the cycle; its synthesis is stimulated by cycle elements, and it, in turn, increases each element of the cycle. is extraordinary �t to the principles of the NO/ONOO − cycle allows one to conclude that PAH is a NO/ONOO − cycle disease, and this �t supports the cycle as a ma�or paradigm of chronic in�ammatory disease.

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The Lbc Rho Guanine Nucleotide Exchange Factor/α-Catulin Axis Functions in Serotonin-induced Vascular Smooth Muscle Cell Mitogenesis and RhoA/ROCK Activation*

Cited by 20 publications

References 48 publications

α-Dystrobrevin-1 recruits α-catulin to the α _1D -adrenergic receptor/dystrophin-associated protein complex signalosome

α-Dystrobrevin-1 recruits α-catulin to the α _1D -adrenergic receptor/dystrophin-associated protein complex signalosome

Mineralocorticoid receptor antagonism attenuates experimental pulmonary hypertension

Pulmonary Hypertension Is a Probable NO/ONOO⁻Cycle Disease: A Review

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The Lbc Rho Guanine Nucleotide Exchange Factor/α-Catulin Axis Functions in Serotonin-induced Vascular Smooth Muscle Cell Mitogenesis and RhoA/ROCK Activation*

Cited by 20 publications

References 48 publications

α-Dystrobrevin-1 recruits α-catulin to the α 1D -adrenergic receptor/dystrophin-associated protein complex signalosome

α-Dystrobrevin-1 recruits α-catulin to the α 1D -adrenergic receptor/dystrophin-associated protein complex signalosome

Mineralocorticoid receptor antagonism attenuates experimental pulmonary hypertension

Pulmonary Hypertension Is a Probable NO/ONOO−Cycle Disease: A Review

Contact Info

Product

Resources

About

α-Dystrobrevin-1 recruits α-catulin to the α _1D -adrenergic receptor/dystrophin-associated protein complex signalosome

α-Dystrobrevin-1 recruits α-catulin to the α _1D -adrenergic receptor/dystrophin-associated protein complex signalosome

Pulmonary Hypertension Is a Probable NO/ONOO⁻Cycle Disease: A Review