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β-adrenergic receptor regulates embryonic epithelial extensibility through actomyosin inhibition.

ABSTRACT: During morphogenesis, epithelial tissues reshape and expand to cover the body and organs. The molecular mechanisms of this deformability remain elusive. Here, we investigate the role of the β-adrenergic receptor (ADRB) in orchestrating actomyosin contractility, pivotal for epithelial extensibility. Chemical screens on Xenopus laevis embryos pinpointed ADRB2 as a principal regulator. ADRB2 promotes actomyosin relaxation, facilitating apical cell area expansion during body elongation. In contrast, ADRB2 knockdown results in heightened cell contraction, marked by synchronous oscillation of F-actin and myosin, impeding body elongation. ADRB2 mutants with reduced affinity for ligand binding lack the function to induce cellular relaxation, highlighting the ligand's essential roles even in the developing epidermis. Our findings unveil ADRB2's critical contribution to extensibility of the epidermis and subsequent body elongation during development. This study also offers insights into the physiology of mature epithelial organs deformed by the smooth muscle response to the adrenergic autonomic nervous system.

SUBMITTER: Mizoguchi Y

PROVIDER: S-EPMC10783608 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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β-adrenergic receptor regulates embryonic epithelial extensibility through actomyosin inhibition.

Mizoguchi Yohei Y Nakashima Kaoru K Sato Ayato A Shindo Asako A

iScience 20231115 12

During morphogenesis, epithelial tissues reshape and expand to cover the body and organs. The molecular mechanisms of this deformability remain elusive. Here, we investigate the role of the β-adrenergic receptor (ADRB) in orchestrating actomyosin contractility, pivotal for epithelial extensibility. Chemical screens on <i>Xenopus laevis</i> embryos pinpointed ADRB2 as a principal regulator. ADRB2 promotes actomyosin relaxation, facilitating apical cell area expansion during body elongation. In co ...[more]

PMID: 38213788

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Project description:BackgroundOncolytic viruses (OVs) are considered a promising therapeutic alternative for cancer. However, OVs could activate the host innate immunity, then impair the viral propagation in tumor cells. In this study, we explored the effect of propranolol, a non-selective β-blocker, on the antitumor efficacy of T1012G virus in gastric cancer models.MethodsThe proliferation of gastric cancer cells treated with monotherapy or combination treatment was detected by CCK8 cell proliferation assay. The effect of propranolol was further evaluated by in vitro viral replication assays. In vivo tumor xenograft experiments were used to observe the effect of combination therapy on gastric cancer growth in mice. The expression levels of viral proteins and interferon responsive genes were detected in the gastric cancer cell lines treated with combined treatment by western blot. The impact of propranolol on IFN-α/β-mediated inhibition of viral propagation and the expression of antiviral gene PKR was detected by viral replication assays and western blot.ResultsCell viability assay detected a 97.9% decrease of T1012G IC50 in HGC-27 when it was pretreated with propranolol along with a sevenfold increase of virus titers compared with T1012G only group (P < 0.001). Moreover, propranolol pretreatment caused sustained tumor regression (335.3 ± 36.92 mm3 vs. 1118 ± 210.0 mm3, P < 0.01) and enhanced the viral propagation (fourfold increase, P < 0.01) compared with T1012G only group. Propranolol pretreatment significantly enhanced the p-STAT3 (2.9-fold, P < 0.05) and suppressed p-PKR (65.94% ± 10.11%, P < 0.05) compared with T1012G only group. In addition, propranolol could counteract IFN-α/β-mediated inhibition of viral propagation (compared with IFNα: 5.1-fold, P < 0.001; IFNβ: 4.6-fold, P < 0.01) or enhancement of PKR activation (IFNα: 92.57% ± 1.77%, P < 0.001, IFNβ: 99.34% ± 0.13% decrease, P < 0.001).ConclusionsIn summary, β-blocker pretreatment could improve the propagation and therapeutic efficacy of T1012G in human gastric cancer by regulating STAT3-PKR signaling cascade, even in the presence of type I IFNs. These data support new strategies of improving the efficacy of OVs in gastric cancer.

Project description:Backgroundβ2-adrenergic receptors (β2ARs) are the target of catecholamines and play fundamental roles in cardiovascular, pulmonary, and skeletal muscle physiology. An important action of β2AR stimulation on skeletal muscle is anabolic growth, which has led to the use of agonists such as clenbuterol by athletes to enhance muscle performance. While previous work has demonstrated that β2ARs can engage distinct signaling and functional cascades mediated by either G proteins or the multifunctional adaptor protein, β-arrestin, the precise role of β-arrestin in skeletal muscle physiology is not known. Here, we tested the hypothesis that agonist activation of the β2AR by clenbuterol would engage β-arrestin as a key transducer of anabolic skeletal muscle growth.MethodsThe contractile force of isolated extensor digitorum longus muscle (EDL) and calcium signaling in isolated flexor digitorum brevis (FDB) fibers were examined from the wild-type (WT) and β-arrestin 1 knockout mice (βarr1KO) followed by chronic administration of clenbuterol (1 mg/kg/d). Hypertrophic responses including fiber composition and fiber size were examined by immunohistochemical imaging. We performed a targeted phosphoproteomic analysis on clenbuterol stimulated primary cultured myoblasts from WT and βarr1KO mice. Statistical significance was determined by using a two-way analysis with Sidak's or Tukey's multiple comparison test and the Student's t test.ResultsChronic administration of clenbuterol to WT mice enhanced the contractile force of EDL muscle and calcium signaling in isolated FDB fibers. In contrast, when administered to βarr1KO mice, the effect of clenbuterol on contractile force and calcium influx was blunted. While clenbuterol-induced hypertrophic responses were observed in WT mice, this response was abrogated in mice lacking β-arrestin 1. In primary cultured myoblasts, clenbuterol-stimulated phosphorylation of multiple pro-hypertrophy proteins required the presence of β-arrestin 1.ConclusionsWe have identified a previously unappreciated role for β-arrestin 1 in mediating β2AR-stimulated skeletal muscle growth and strength. We propose these findings could have important implications in the design of future pharmacologic agents aimed at reversing pathological conditions associated with skeletal muscle wasting.

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β-adrenergic receptor regulates embryonic epithelial extensibility through actomyosin inhibition.

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β-adrenergic receptor regulates embryonic epithelial extensibility through actomyosin inhibition.

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