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Neuroblastoma (NB), the most common extracranial solid tumor in childhood, always leads to an unfavorable prognosis. β3-adrenergic receptor (β3-AR) signaling plays an important role in lipid metabolism. Although previous studies have focused mainly on the role of β2-AR in tumor cells; there are few studies about the cancer-related function of β3-AR. Herein, we showed that β3-AR expression was significantly increased in clinical NB tissue compared with that in the less malignant ganglioneuroma (GN) and ganglioneuroblastoma (GNB) tissues. Further cellular assays demonstrated that treatment of NB cells with SR59230A (a specific β3-AR antagonist) suppressed NB cells growth and colony formation, and siRNA knockdown of β3-AR expression also inhibited NB cell proliferation. The mechanistic study revealed that β3-AR knockdown and SR59230A inhibited the phosphorylation and thereby the activation of the mTOR/p70S6K pathway. Activation of the mTOR pathway with the activator MHY1485 reversed the inhibitory effect of SR59230A on NB cell growth. Above all, our study clarifies a novel regulatory role of β3-AR in NB cell growth and provides a potent therapeutic strategy for this disease by specific targeting of the β3-AR pathway., (Copyright © 2019. Published by Elsevier Inc.)

In heart failure, the expression of cardiac β 3 -adrenergic receptors (β 3 -ARs) increases. However, the precise role of β 3 -AR signaling within cardiomyocytes remains unclear. Transforming growth factor β1 (TGFβ1) is a crucial cytokine mediating the cardiac remodeling that plays a causal role in the progression of heart failure. Here, we set out to determine the effect of β 3 -AR activation on TGFβ1 expression in rat cardiomyocytes and examine the underlying mechanism. The selective β 3 -AR agonist BRL37344 induced an increase in TGFβ1 expression and the phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun in β 3 -AR-overexpressing cardiomyocytes. Those effects of BRL37344 were suppressed by a β 3 -AR antagonist. Moreover, the inhibition of JNK and c-Jun activity by a JNK inhibitor and c-Jun siRNA blocked the increase in TGFβ1 expression upon β 3 -AR activation. A protein kinase G (PKG) inhibitor also attenuated β 3 -AR-agonist-induced TGFβ1 expression and the phosphorylation of JNK and c-Jun. In conclusion, the β 3 -AR activation in cardiomyocytes increases the expression of TGFβ1 via the PKG/JNK/c-Jun pathway. These results help us further understand the role of β 3 -AR signaling in heart failure., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Nebivolol is a third-generation β-adrenergic receptor (β-AR) blocker with additional beneficial effects, including the improvement of lipid and glucose metabolism in obese individuals. However, the underlying mechanism of nebivolol's role in regulating the lipid profile remains largely unknown. In this study, we investigated the role of nebivolol in mitochondrial biogenesis in 3T3-L1 adipocytes. Exposure of 3T3-L1 cells to nebivolol for 24h increased mitochondrial DNA copy number, mitochondrial protein levels and the expression of transcription factors involved in mitochondrial biogenesis, including PPAR-γ coactivator-1α (PGC-1α), Sirtuin 3 (Sirt3), mitochondrial transcription factor A (Tfam) and nuclear related factor 1 (Nrf1). These changes were accompanied by an increase in oxygen consumption and in the expression of genes involved in fatty acid oxidation and antioxidant enzymes in 3T3-L1 adipocytes, including nebivolol-induced endothelial nitric oxide synthase (eNOS), as well as an increase in the formation of cyclic guanosine monophosphate (cGMP). Pretreatment with NG-nitro-L-arginine methyl ester (L-NAME) attenuated nebivolol-induced mitochondrial biogenesis, as did the soluble guanylate cyclase inhibitor, ODQ. Treatment with nebivolol and β3-AR blocker SR59230A markedly attenuated PGC-1α, Sirt3 and manganese superoxide dismutase (MnSOD) protein levels in comparison to treatment with nebivolol alone. These data indicate that the mitochondrial synthesis and metabolism in adipocytes that is promoted by nebivolol is primarily mediated through the eNOS/cGMP-dependent pathway and is initiated by the activation of β3-AR receptors., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Kir2.x channels form the molecular basis of cardiac I(K1) current and play a major role in cardiac electrophysiology. However, there is a substantial lack of selective Kir2 antagonists. We found the β(3)-adrenoceptor antagonist SR59230A to be an inhibitor of Kir2.x channels. Therefore, we characterized the effects of SR59230A on Kir2.x and other relevant cardiac potassium channels. Cloned channels were expressed in the Xenopus oocyte expression system and measured with the double-microelectrode voltage clamp technique. SR59230A inhibited homomeric Kir2.1 channels with an IC(50) of 33μM. Homomeric Kir2.2 and Kir2.3 channels and Kir2.x heteromers were also inhibited by SR59230A with similar potency. In contrast, no relevant inhibitory effects of SR59230A were found in cardiac Kv1.5, Kv4.3 and KvLQT1/minK channels. In hERG channels, SR59230A only induced a weak inhibition at a high concentration. These findings establish SR59230A as a novel inhibitor of Kir2.1-2.3 channels with a favorable profile with respect to additional effects on other cardiac repolarizing potassium channels., (Copyright © 2012 Elsevier Inc. All rights reserved.)