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CAMP-dependent cell differentiation triggered by activated CRHR1 in hippocampal neuronal cells.

ABSTRACT: Corticotropin-releasing hormone receptor 1 (CRHR1) activates the atypical soluble adenylyl cyclase (sAC) in addition to transmembrane adenylyl cyclases (tmACs). Both cAMP sources were shown to be required for the phosphorylation of ERK1/2 triggered by activated G protein coupled receptor (GPCR) CRHR1 in neuronal and neuroendocrine contexts. Here, we show that activated CRHR1 promotes growth arrest and neurite elongation in neuronal hippocampal cells (HT22-CRHR1 cells). By characterising CRHR1 signalling mechanisms involved in the neuritogenic effect, we demonstrate that neurite outgrowth in HT22-CRHR1 cells takes place by a sAC-dependent, ERK1/2-independent signalling cascade. Both tmACs and sAC are involved in corticotropin-releasing hormone (CRH)-mediated CREB phosphorylation and c-fos induction, but only sAC-generated cAMP pools are critical for the neuritogenic effect of CRH, further highlighting the engagement of two sources of cAMP downstream of the activation of a GPCR, and reinforcing the notion that restricted cAMP microdomains may regulate independent cellular processes.

SUBMITTER: Inda C

PROVIDER: S-EPMC5434020 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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cAMP-dependent cell differentiation triggered by activated CRHR1 in hippocampal neuronal cells.

Inda Carolina C Bonfiglio Juan José JJ Dos Santos Claro Paula A PA Senin Sergio A SA Armando Natalia G NG Deussing Jan M JM Silberstein Susana S

Scientific reports 20170516 1

Corticotropin-releasing hormone receptor 1 (CRHR1) activates the atypical soluble adenylyl cyclase (sAC) in addition to transmembrane adenylyl cyclases (tmACs). Both cAMP sources were shown to be required for the phosphorylation of ERK1/2 triggered by activated G protein coupled receptor (GPCR) CRHR1 in neuronal and neuroendocrine contexts. Here, we show that activated CRHR1 promotes growth arrest and neurite elongation in neuronal hippocampal cells (HT22-CRHR1 cells). By characterising CRHR1 si ...[more]

PMID: 28512295

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Project description:Protein inhibitor of activated STAT1 (PIAS1), a small ubiquitin-like modifier (SUMO) E3 ligase, was considered to be an inhibitor of STAT1 by inhibiting the DNA-binding activity of STAT1 and blocking STAT1-mediated gene transcription in response to cytokine stimulation. PIAS1 has been determined to be involved in modulating several biological processes such as cell proliferation, DNA damage responses, and inflammatory responses, both in vivo and in vitro. However, the role played by PIAS1 in regulating neurodegenerative diseases, including Alzheimer's disease (AD), has not been determined. In our study, significantly different expression levels of PIAS1 between normal controls and AD patients were detected in four regions of the human brain. Based on a functional analysis of Pias1 in undifferentiated mouse hippocampal neuronal HT-22 cells, we observed that the expression levels of several AD marker genes could be inhibited by Pias1 overexpression. Moreover, the proliferation ability of HT-22 cells could be promoted by the overexpression of Pias1. Furthermore, we performed RNA sequencing (RNA-seq) to evaluate and quantify the gene expression profiles in response to Pias1 overexpression in HT-22 cells. As a result, 285 significantly dysregulated genes, including 79 upregulated genes and 206 downregulated genes, were identified by the comparison of Pias1/+ cells with WT cells. Among these genes, five overlapping genes, including early growth response 1 (Egr1), early growth response 2 (Egr2), early growth response 3 (Egr3), FBJ osteosarcoma oncogene (Fos) and fos-like antigen 1 (Fosl1), were identified by comparison of the transcription factor binding site (TFBS) prediction results for STAT1, whose expression was evaluated by qPCR. Three cell cycle inhibitors, p53, p18 and p21, were significantly downregulated with the overexpression of Pias1. Analysis of functional enrichment and expression levels showed that basic region leucine zipper domain-containing transcription factors including zinc finger C2H2 (zf-C2H2), homeobox and basic/helix-loop-helix (bHLH) in several signaling pathways were significantly involved in PIAS1 regulation in HT-22 cells. A reconstructed regulatory network under PIAS1 overexpression demonstrated that there were 43 related proteins, notably Nr3c2, that directly interacted with PIAS1.

Dataset Information

CAMP-dependent cell differentiation triggered by activated CRHR1 in hippocampal neuronal cells.

Publications

cAMP-dependent cell differentiation triggered by activated CRHR1 in hippocampal neuronal cells.

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