Munc13 Is a Molecular Target of Bryostatin 1
| العنوان: | Munc13 Is a Molecular Target of Bryostatin 1 |
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| المؤلفون: | Gary A. Mitchell, Agnes Czikora, Noemi Kedei, Joydip Das, Satyabrata Pany, Peter M. Blumberg, Francisco A Blanco, Anamitra Ghosh, Youngki You |
| المصدر: | Biochemistry. 58:3016-3030 |
| بيانات النشر: | American Chemical Society (ACS), 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Models, Molecular, Neurons, Binding Sites, Bryostatin 1, Chemistry, Nerve Tissue Proteins, Plasma protein binding, Bryostatins, Biochemistry, In vitro, Cell Line, Cell biology, Molecular Docking Simulation, Mice, Mechanism of action, Cell culture, Phorbol Esters, medicine, Animals, medicine.symptom, Protein kinase A, Cells, Cultured, Protein kinase C, Protein Binding, C1 domain |
| الوصف: | [Image: see text] Bryostatin 1 is a natural macrolide shown to improve neuronal connections and enhance memory in mice. Its mechanism of action is largely attributed to the modulation of novel and conventional protein kinase Cs (PKCs) by binding to their regulatory C1 domains. Munc13-1 is a C1 domain-containing protein that shares common endogenous and exogenous activators with novel and conventional PKC subtypes. Given the essential role of Munc13-1 in the priming of synaptic vesicles and neuronal transmission overall, we explored the potential interaction between bryostatin 1 and Munc13-1. Our results indicate that in vitro bryostatin 1 binds to both the isolated C1 domain of Munc13-1 (K(i) = 8.07 ± 0.90 nM) and the full-length Munc13-1 protein (K(i) = 0.45 ± 0.04 nM). Furthermore, confocal microscopy and immunoblot analysis demonstrated that in intact HT22 cells bryostatin 1 mimics the actions of phorbol esters, a previously established class of Munc13-1 activators, and induces plasma membrane translocation of Munc13-1, a hallmark of its activation. Consistently, bryostatin 1 had no effect on the Munc13-1(H567K) construct that is insensitive to phorbol esters. Effects of bryostatin 1 on the other Munc13 family members, ubMunc13-2 and bMunc13-2, resembled those of Munc13-1 for translocation. Lastly, we observed an increased level of expression of Munc13-1 following a 24 h incubation with bryostatin 1 in both HT22 and primary mouse hippocampal cells. This study characterizes Munc13-1 as a molecular target of bryostatin 1. Considering the crucial role of Munc13-1 in neuronal function, these findings provide strong support for the potential role of Munc13s in the actions of bryostatin 1. |
| تدمد: | 1520-4995 0006-2960 |
| DOI: | 10.1021/acs.biochem.9b00427 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b044f539cfd05011b3040672cf6ad615 https://doi.org/10.1021/acs.biochem.9b00427 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b044f539cfd05011b3040672cf6ad615 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15204995 00062960 |
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| DOI: | 10.1021/acs.biochem.9b00427 |