Thyroid Hormone-Induced Differentiation of Astrocytes is Associated with Transcriptional Upregulation of β-arrestin-1 and β-adrenergic Receptor-Mediated Endosomal Signaling

Abstract

Thyroid hormones (TH) promote differentiation of astrocytes. We have previously reported that a downstream role β-adrenergic receptor (β-AR) system in such effects of TH. Although evidences indicate strong interaction between TH and the β-ARs, the underlying mechanism is poorly understood. In the present study, we further explored the influence of TH on β-AR signaling during the differentiation process. Unlike β1-AR, binding of (125)I-pindolol to β2-AR in cell membranes was significantly decreased at 2 h of exposure to TH which came back to control values after 24 h. The initial decrease in β2-AR in membranes resulted in a concomitant increase in β2-AR levels in the cytosol, suggesting that TH may induce endocytosis of the receptor. qRT-PCR as well as Western blot analysis demonstrated that unlike β-adrenergic receptor kinase (β-ARK)1 and β-ARK2, the messenger RNA (mRNA) and protein levels of β-arrestin-1 in the astrocyte cultures increased on exposure to TH. Knockdown of β-arrestin gene suggested requirement of both β-arrestin-1 and β-arrestin-2 isoforms during endocytosis of β2-AR, thereby facilitating cell differentiation. Endocytic inhibitors blocked the delayed but sustained activation of p-extracellular signal-regulated kinase (ERK) observed during cell differentiation. Observations suggest that TH upregulate β-arrestin-1 in astrocytes to facilitate endocytosis of β2-AR, required for endosomal ERK activation to drive the differentiation process.

Beta‐arrestin 2 mediates cardiac hypertrophy induced by thyroid hormones via AT1R

“…Li et al, 2002). Moreover, another study showed that ARRB2 plays a critical role in the differentiation of astrocytes induced by TH (Das et al, 2016). In our study, we verified that T3 upregulated the transcription of both ARRBs and increased ARRB2 protein expression in cardiomyocytes.…”

“…They showed the regulation of visual arrestins by retinoic acid (nuclear receptors of TH and retinoic acid are usually found as heterodimers in the nucleus to regulate gene transcription; Li et al, 2002). Moreover, another study showed that ARRB2 plays a critical role in the differentiation of astrocytes induced by TH (Das et al, 2016). In our study, we verified that T3 upregulated the transcription of both ARRBs and increased ARRB2 protein expression in cardiomyocytes.…”

β‐Arrestin1‐mediated decrease in endoplasmic reticulum stress impairs intestinal stem cell proliferation following radiation

“…b-arrestin1 (barr1) is a ubiquitous multifunctional adaptor protein that acts as a scaffold and adaptor to regulate cell proliferation, apoptosis, and differentiation (12)(13)(14). Our previous research has shown that barr1 has a close relationship with ER stress pathways and that barr1 inhibited ER stress and the PUMA pathway via restriction of the induced nitric oxide synthase (iNOS)/phosphorylated P65 (p-P65) axis, reducing gastric mucosa apoptosis in portal hypertension gastropathy (15).…”

Role of ARRB1 in prognosis and immunotherapy: A Pan-Cancer analysis

“…Beta-arrestin1 (ARRB1), belonging to the arrestin family of proteins, was originally identified as an adaptor protein that regulates G protein-coupled receptor (GPCR) desensitization and internalization (Kang et al, 2005). ARRB1 is now known to be a ubiquitous adaptor protein that plays a role in the regulation of cell proliferation, differentiation, autophagy, and apoptosis (Yang et al, 2015;Das et al, 2016;Zhan et al, 2016;Lei et al, 2021). In addition to cytoplasmic functions, the nuclear activity of ARRB1 has recently been reported (Hoeppner et al, 2012;Purayil et al, 2015) and is thought to be a nuclear transcriptional regulator of the endothelin-1-induced β-catenin signaling (Rosanò et al, 2013).…”