Heterotrimeric G Stimulatory Protein α Subunit Is Required for Intestinal Smooth Muscle Contraction in Mice

Qin, Xiaoteng; Liu, Shangming; Lu, Qiulun; Zhang, Meng; Jiang, Xiuxin; Hu, Sanyuan; Li, Jingxin; Zhang, Cheng; Gao, Jiangang; Zhu, Min–Sheng; Feil, Robert; Li, Huashun; Chen, Min; Weinstein, Lee S.; Zhang, Yun; Zhang, Wencheng

doi:10.1053/j.gastro.2016.12.017

Cited by 17 publications

(13 citation statements)

References 23 publications

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“…Moreover, consideration about the synthetic phenotype of Gsα-deficient smooth muscle cells, Gsα deletion might increase the angiogenesis and reduce the vascular resistance in the small vessels. In our previous study, Gsα deficiency impaired intestinal smooth muscle contraction [20], which affect their food intake. Thus, Gsa SMKO mice exhibited the phenotype of lower body weight.…”

Section: Discussionmentioning

confidence: 88%

“…However, mice overexpressing a dominant negative Gsα-mutant in heart leads to decreased β-adrenergic responsiveness and is protective against ISO-induced hypertrophy [19]. In our recent report, we found that Gsα could regulate intestinal smooth muscle contraction in mice [20]. However, the roles of Gsα in the SMC phenotype switch and AAA formation are undefined.…”

Section: Introductionmentioning

confidence: 99%

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Smooth muscle-specific Gsα deletion exaggerates angiotensin II-induced abdominal aortic aneurysm formation in mice in vivo

Qin

Tian

et al. 2019

Journal of Molecular and Cellular Cardiology

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Objective: Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease without an effective pharmaceutical treatment. Genetic studies have proved the involvement of smooth muscle phenotype switch in the development of AAA. The alpha subunit of the heterotrimeric G stimulatory protein (Gsα) mediates receptorstimulated production of cyclic adenosine monophosphate (cAMP). However, the role of smooth muscle Gsα in AAA formation remains unknown. Approach and results: In this study, mice with knockout of smooth muscle-specific Gsα (Gsα SMKO ) were generated by cross-breeding Gsα flox/flox mice with SM22-CreER T2 transgenic mice, induced in adult mice by tamoxifen treatment. Gsα deficiency induced a smooth muscle phenotype switch from a contractile to a synthetic state. Mechanically, Gsα deletion reduced cAMP level and increased the level of human antigen R (HuR), which binds with the adenylate uridylate-rich elements of the 3′ untranslated region of Krüppel-like factor 4 (KLF4) mRNA, thereby increasing the stability of KLF4. Moreover, genetic knockdown of HuR or KLF4 rescued the phenotype switch in Gsα-deficient smooth muscle cells. Furthermore, with acute infusion of angiotensin II, the incidence of AAA was markedly higher in ApoE −/− /Gsα SMKO than ApoE −/− /Gsα flox/flox mice and induced increased elastic lamina degradation and aortic expansion. Finally, the levels of Gsα and SM α-actin were significantly lower while those of HuR and KLF4 were higher in human AAA samples than adjacent nonaneurysmal aortic sections. Conclusions: Gsα may play a protective role in AAA formation by regulating the smooth muscle phenotype switch and could be a potential therapeutic target for AAA disease.is often accompanied by downregulation of multiple contractile proteins in aortic smooth muscle cells (SMCs) [4,5]. Furthermore, aortic intimal layer injury and inflammatory cell infiltration participate in the aneurysm progression via complicated mechanisms such as cytokine secretion and increased reactive oxygen species levels [3,6]. Finally, vascular collagen and elastin extracellular matrix is thought to undergo degradation by matrix metalloproteinases and contribute to AAA

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Smooth muscle-specific Gsα deletion exaggerates angiotensin II-induced abdominal aortic aneurysm formation in mice in vivo

Qin

Tian

et al. 2019

Journal of Molecular and Cellular Cardiology

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“…The contraction in the smooth muscle of the intestine in response to various agents is often composed of two phases: phasic, fast, and unsustainable component followed by a tonic, slow, and sustained component. The mechanism responsible for the phasic component is related to the activation of a metabotropic receptor coupled to protein G. On the other hand, the tonic component is mainly mediated by calcium influx through voltage-dependent calcium channels (Ca V ) (Bolton, 1979;van Breemen & Saida, 1989;Murthy, 2006;Sakamoto et al, 2007;Qin et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Hydroalcoholic extract of leaves of Arrabidaea brachypoda (DC.) Bureau present antispasmodic activity mediated through calcium influx blockage

Monteiro

Costa

Martins³

et al. 2020

Rev. Ciênc. Farm. Básica Apl.

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Aim: Since other species of the Bignoniaceae Family presented of antispasmodic activity, it was decided, by chemotaxonomic criterion, to determine the antispasmodic activity of the leaves of Arrabidaea brachypoda. Methodology: the segments of the rat jejunum were suspended in glass vats containing specific saline solution, at an appropriate temperature, and after stabilization period, were stimulated by a contractile agent to observe the inhibitory or relaxing effect of EH-FAB. Results: EH-FAB showed the presence of 10 compounds, mainly rutin and it has an antispasmodic activity as it inhibits the phasic component and relaxes the tonic component of the contraction in isolated rat jejunum. To assess the mechanism of antispasmodic action, cumulative curves to the CCh were performed in which a non-competitive antagonism was observed, due to a displacement of the control curve to the right and reduction of the maximum contraction effect (E max). Afterward, the participation of the calcium and/or potassium channels was evaluated by increasing the extracellular potassium, and it was observed that the EH-FAB relaxed the rat jejunum, suggesting the participation of the Ca 2+ channels. To corroborate that hypothesis, the EH-FAB was tested against cumulative curves to Ca 2+ in a free depolarizing solution of Ca 2+ , and it was observed that there was a shift of the curve to the right with a reduction in E max. Conclusions: EH-FAB presents antispasmodic activity in isolated rat jejunum and it is suggested to block the influx of Ca 2+ through voltage-gated calcium channels, signaling the therapeutic potential for the treatment of colic and/or diarrhea.

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“…Until now, most of the research has been devoted to understanding adenosinesignaling in the myenteric plexus; however, data concerning the physiological relevance of AMP and related ecto-enzymes CD73 and ADA in controlling adenosine levels in gut IMFs are still limited [8-10, 15, 19]. Smooth muscle myopathies have been observed in various gastrointestinal diseases, including chronic intestinal pseudo-obstruction (CIP) [26] and inflammatory bowel disease (IBD) [27][28][29]. IMFs show morphologic and functional features of both fibroblasts and smooth muscle cells and appear to transdifferentiate from these cells or to originate from primitive stem cells.…”

Section: Discussionmentioning

confidence: 99%

The ecto-enzymes CD73 and adenosine deaminase modulate 5′-AMP-derived adenosine in myofibroblasts of the rat small intestine

Bin

Caputi

Bistoletti

et al. 2018

Purinergic Signalling

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Adenosine is a versatile signaling molecule recognized to physiologically influence gut motor functions. Both the duration and magnitude of adenosine signaling in enteric neuromuscular function depend on its availability, which is regulated by the ectoenzymes ecto-5′-nucleotidase (CD73), alkaline phosphatase (AP), and ecto-adenosine deaminase (ADA) and by dipyridamolesensitive equilibrative transporters (ENTs). Our purpose was to assess the involvement of CD73, APs, ecto-ADA in the formation of AMP-derived adenosine in primary cultures of ileal myofibroblasts (IMFs). IMFs were isolated from rat ileum longitudinal muscle segments by means of primary explant technique and identified by immunofluorescence staining for vimentin and αsmooth muscle actin. IMFs confluent monolayers were exposed to exogenous 5′-AMP in the presence or absence of CD73, APs, ecto-ADA, or ENTs inhibitors. The formation of adenosine and its metabolites in the IMFs medium was monitored by highperformance liquid chromatography. The distribution of CD73 and ADA in IMFs was detected by confocal immunocytochemistry and qRT-PCR. Exogenous 5′-AMP was rapidly cleared being almost undetectable after 60-min incubation, while adenosine levels significantly increased. Treatment of IMFs with CD73 inhibitors markedly reduced 5′-AMP clearance whereas ADA blockade or inhibition of both ADA and ENTs prevented adenosine catabolism. By contrast, inhibition of APs did not affect 5′-AMP metabolism. Immunofluorescence staining and qRT-PCR analysis confirmed the expression of CD73 and ADA in IMFs. Overall, our data show that in IMFs an extracellular AMP-adenosine pathway is functionally active and among the different enzymatic pathways regulating extracellular adenosine levels, CD73 and ecto-ADA represent the critical catabolic pathway.

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Heterotrimeric G Stimulatory Protein α Subunit Is Required for Intestinal Smooth Muscle Contraction in Mice

Abstract: Gsa is required for intestinal smooth muscle contraction in mice, and its levels are reduced in ileum biopsies of patients with chronic intestinal pseudo-obstruction. Mice with disruption of Gnas might be used to study human chronic intestinal pseudo-obstruction.

Cited by 17 publications

References 23 publications

Smooth muscle-specific Gsα deletion exaggerates angiotensin II-induced abdominal aortic aneurysm formation in mice in vivo

Smooth muscle-specific Gsα deletion exaggerates angiotensin II-induced abdominal aortic aneurysm formation in mice in vivo

Hydroalcoholic extract of leaves of Arrabidaea brachypoda (DC.) Bureau present antispasmodic activity mediated through calcium influx blockage

The ecto-enzymes CD73 and adenosine deaminase modulate 5′-AMP-derived adenosine in myofibroblasts of the rat small intestine

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