دورية أكاديمية
Metformin inhibits nerve growth factor-induced sympathetic neuron differentiation through p35/CDK5 inhibition.
| العنوان: | Metformin inhibits nerve growth factor-induced sympathetic neuron differentiation through p35/CDK5 inhibition. |
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| المؤلفون: | Oner M; Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan., Chen MC; Department of Medical Research, Translational Cell Therapy Center, China Medical University Hospital, Taichung, Taiwan., Cheng PT; Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan., Lin H; Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan. |
| المصدر: | American journal of physiology. Cell physiology [Am J Physiol Cell Physiol] 2024 Jun 01; Vol. 326 (6), pp. C1648-C1658. Date of Electronic Publication: 2024 Apr 29. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Physiological Society Country of Publication: United States NLM ID: 100901225 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1563 (Electronic) Linking ISSN: 03636143 NLM ISO Abbreviation: Am J Physiol Cell Physiol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Bethesda, Md. : American Physiological Society, |
| مواضيع طبية MeSH: | Metformin*/pharmacology , Cyclin-Dependent Kinase 5*/metabolism , Cyclin-Dependent Kinase 5*/antagonists & inhibitors , Nerve Growth Factor*/metabolism , Nerve Growth Factor*/pharmacology , Receptor, trkA*/metabolism , Receptor, trkA*/antagonists & inhibitors , Neurons*/drug effects , Neurons*/metabolism , Cell Differentiation*/drug effects, Animals ; Rats ; PC12 Cells ; Signal Transduction/drug effects ; Neurogenesis/drug effects ; Early Growth Response Protein 1/metabolism ; Early Growth Response Protein 1/genetics ; Nerve Tissue Proteins/metabolism ; Nerve Tissue Proteins/genetics ; Phosphotransferases |
| مستخلص: | The authors' previous research has shown the pivotal roles of cyclin-dependent kinase 5 (CDK5) and its regulatory protein p35 in nerve growth factor (NGF)-induced differentiation of sympathetic neurons in PC12 cells. During the process of differentiation, neurons are susceptible to environmental influences, including the effects of drugs. Metformin is commonly used in the treatment of diabetes and its associated symptoms, particularly in diabetic neuropathy, which is characterized by dysregulation of the sympathetic neurons. However, the impacts of metformin on sympathetic neuronal differentiation remain unknown. In this study, we investigated the impact of metformin on NGF-induced sympathetic neuronal differentiation using rat pheochromocytoma PC12 cells as a model. We examined the regulation of TrkA-p35/CDK5 signaling in NGF-induced PC12 differentiation. Our results demonstrate that metformin reduces NGF-induced PC12 differentiation by inactivating the TrkA receptor, subsequently inhibiting ERK and EGR1. Inhibition of this cascade ultimately leads to the downregulation of p35/CDK5 in PC12 cells. Furthermore, metformin inhibits the activation of the presynaptic protein Synapsin-I, a substrate of CDK5, in PC12 differentiation. In addition, metformin alters axonal and synaptic bouton formation by inhibiting p35 at both the axons and axon terminals in fully differentiated PC12 cells. In summary, our study elucidates that metformin inhibits sympathetic neuronal differentiation in PC12 cells by disrupting TrkA/ERK/EGR1 and p35/CDK5 signaling. This research contributes to uncovering a novel signaling mechanism in drug response during sympathetic neuronal differentiation, enhancing our understanding of the intricate molecular processes governing this critical aspect of neurodevelopment. NEW & NOTEWORTHY This study unveils a novel mechanism influenced by metformin during sympathetic neuronal differentiation. By elucidating its inhibitory effects from the nerve growth factor (NGF) receptor, TrkA, to the p35/CDK5 signaling pathways, we advance our understanding of metformin's mechanisms of action and emphasize its potential significance in the context of drug responses during sympathetic neuronal differentiation. |
| معلومات مُعتمدة: | 109-2320-B-005-004-MY3 National Science and Technology Council (NSTC); 112-2320-B-005-008 National Science and Technology Council (NSTC); 109-2911-I-005-503 National Science and Technology Council (NSTC); TCVGH-NCHU1117614 Taichung Veterans General Hospital (TCVGH); (TTMHH-R1120062),(TTMHH-NCHULS112004) Tung's Taichung metro harbor hospital |
| فهرسة مساهمة: | Keywords: PC12; cyclin-dependent kinase 5 (CDK5); metformin; nerve growth factor (NGF); sympathetic neuronal differentiation |
| المشرفين على المادة: | 9100L32L2N (Metformin) EC 2.7.11.1 (Cyclin-Dependent Kinase 5) 9061-61-4 (Nerve Growth Factor) EC 2.7.11.22 (Cdk5 protein, rat) EC 2.7.10.1 (Receptor, trkA) 0 (Early Growth Response Protein 1) 0 (Egr1 protein, rat) 0 (Cdk5r1 protein, rat) 0 (Nerve Tissue Proteins) EC 2.7.- (Phosphotransferases) |
| تواريخ الأحداث: | Date Created: 20240429 Date Completed: 20240606 Latest Revision: 20240905 |
| رمز التحديث: | 20240905 |
| DOI: | 10.1152/ajpcell.00121.2024 |
| PMID: | 38682237 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1522-1563 |
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| DOI: | 10.1152/ajpcell.00121.2024 |