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Gintonin stimulates dendritic growth in striatal neurons by activating Akt and CREB.

ABSTRACT: Gintonin, a glycolipid protein conjugated with lysophosphatidic acid (LPA), is a newly identified compound extracted from Korean ginseng. LPA receptor isotypes exhibit high affinity for gintonin and mediate intracellular calcium signaling in various animal cell models. In this study, we found that gintonin induced the activation of Akt and cAMP-response element binding protein (CREB) in mouse striatal neurons, and chronic treatment with gintonin potently induced dendritic growth and filopodia formation. Gintonin-induced Akt/CREB activation and dendritic development were significantly impaired by LPA receptor (LPAR1/3) inhibition with Ki16425. Intriguingly, prolonged treatment with gintonin ameliorated the reduction in dendritic formation caused by Shank3 and Slitrk5 deficiency in the striatal neurons. In addition, gintonin and brain-derived neurotrophic factor (BDNF) had a synergistic effect on AKT/CREB activation and dendritic growth at suboptimal concentrations. These findings imply that gintonin-stimulated LPA receptors play a role in dendritic growth in striatal neurons and that they may act synergistically with BDNF, which is known to play a role in dendritogenesis.

SUBMITTER: Lim HK

PROVIDER: S-EPMC9643712 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Gintonin stimulates dendritic growth in striatal neurons by activating Akt and CREB.

Lim Hye Kyung HK Kim Kitaek K Son Youn Kyoung YK Nah Seung-Yeol SY Ahn Soo Min SM Song Minseok M

Frontiers in molecular neuroscience 20221026

Gintonin, a glycolipid protein conjugated with lysophosphatidic acid (LPA), is a newly identified compound extracted from Korean ginseng. LPA receptor isotypes exhibit high affinity for gintonin and mediate intracellular calcium signaling in various animal cell models. In this study, we found that gintonin induced the activation of Akt and cAMP-response element binding protein (CREB) in mouse striatal neurons, and chronic treatment with gintonin potently induced dendritic growth and filopodia fo ...[more]

PMID: 36385759

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Project description:AimsThe neurotropic growth factor PDGF-BB was shown to have vital neurorestorative functions in various animal models of Parkinson's disease (PD). Previous studies indicated that the regenerative property of PDGF-BB contributes to the increased intensity of tyrosine hydroxylase (TH) fibers in vivo. However, whether PDGF-BB directly modulates the expression of TH, and the underlying mechanism is still unknown. We will carefully examine this in our current study.MethodMPTP-lesion mice received PDGF-BB treatment via intracerebroventricular (i.c.v) administration, and the expression of TH in different brain regions was assessed by RT-PCR, Western blot, and immunohistochemistry staining. The molecular mechanisms of PDGF-BB-mediated TH upregulation were examined by RT-PCR, Western blot, ChIP assay, luciferase reporter assay, and immunocytochemistry.ResultsWe validated a reversal expression of TH in MPTP-lesion mice upon i.c.v administration of PDGF-BB for seven days. Similar effects of PDGF-BB-mediated TH upregulation were also observed in MPP+ -treated primary neuronal culture and dopaminergic neuronal cell line SH-SY5Y cells. We next demonstrated that PDGF-BB rapidly activated the pro-survival PI3K/Akt and MAPK/ERK signaling pathways, as well as the downstream CREB in SH-SY5Y cells. We further confirmed the significant induction of p-CREB in PDGF-BB-treated animals in vivo. Using a genetic approach, we demonstrated that the transcription factor CREB is critical for PDGF-BB-mediated TH expression. The activation and nucleus translocation of CREB were promoted in PDGF-BB-treated SH-SY5Y cells, and the enrichment of CREB on the promoter region of TH gene was also increased upon PDGF-BB treatment.ConclusionOur data demonstrated that PDGF-BB directly regulated the expression of TH via activating the downstream Akt/ERK/CREB signaling pathways. Our finding will further support the therapeutic potential of PDGF-BB in PD, and provide the possibility that targeting PDGF signaling can be harnessed as an adjunctive therapy in PD in the future.

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Gintonin stimulates dendritic growth in striatal neurons by activating Akt and CREB.

Publications

Gintonin stimulates dendritic growth in striatal neurons by activating Akt and CREB.

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