Geranylgeranyltransferase I (GGT) is a prenyltransferase that mediates lipid modification of Rho small GTPases, such as Rho, Rac, and Cdc42, which are important for neuronal synaptogenesis. Although GGT is expressed in brain extensively, the function of GGT in central nerves system is largely unknown so far. We have previously demonstrated that GGT promotes the basal and neuronal activity and brain-derived neurotrophic factor (BDNF)-induced dendritic morphogenesis of cultured hippocampal neurons and cerebellar slices. This study is to explore the function and mechanism of GGT in neuronal synaptogenesis. We found that the protein level and activity of GGT gradually increased in rat hippocampus from P7 to P28 and subcellular located at synapse of neurons. The linear density of Synapsin 1 and post-synaptic density protein 95 increased by over-expression of GGT b, while reduced by inhibition or down-regulation of GGT. In addition, GGT and its known substrate Rac was activated by BDNF, which promotes synaptogenesis in cultured hippocampal neurons. Furthermore, BDNF-induced synaptogenesis was eliminated by GGT inhibition or down-regulation, as well as by non-prenylated Rac1 over-expression. Together, our data suggested that GGT mediates BDNF-induced neuronal synaptogenesis through Rac1 activation. Keywords: brain-derived neurotrophic factor, geranylgeranyltransferase I, post-synaptic density protein 95, Rac, Synapsin 1, synaptogenesis. As key regulators of the actin cytoskeleton, members of the Rho-family GTPases, including Rac1, Cdc42, and RhoA, which play essential roles in orchestrating the Abbreviations used: BDNF, brain-derived neurotrophic factor; FT, farnesyltransferase; GEFs, guanine nucleotide exchange factors; GGT, geranylgeranyltransferase I; PBS, phosphate buffered saline; PSD 95, post-synaptic density protein 95; TrkB, tropomyosin-related kinase B.
Geranylgeranyltransferase I (GGT), a protein prenyltransferase, is responsible for the posttranslational lipidation of Rho GTPases, such as Rac, Rho and Cdc42, all of which play an important role in neuronal synaptogenesis. We previously demonstrated that GGT promotes dendritic morphogenesis in cultured hippocampal neurons and cerebellar slices. We report here that inhibiting GGT activity decreases basal- and activity-dependent changes in spine density as well as in learning and memory ability of mice in vivo. We found that KCl- or bicuculline-induced dendritic spine density increases was abolished by specific GGT inhibitor GGTi-2147 treatment in cultured hippocampal neurons. GGTi-2147 lateral ventricular injection reduced GGT activity and membrane association of Rac and decreased the density of dendritic spines in the mouse hippocampus, frontal cortex and cerebellum. GGTi-2147 administration also impaired learning and memory ability of mice. More importantly, mice exposed to environmental enrichment (EE) showed increased spine density and learning and memory ability, which were significantly reversed by GGTi-2147 administration. These data demonstrate that inhibiting GGT activity prevents both basal- and activity-dependent changes in spine density in central nervous system both in vitro and in vivo. Manipulating GGT activity may be a promising strategy for the therapies of neurodevelopmental disorders, such as autism, depression, and schizophrenia.
Purpose: To study the antimicrobial activity of the Taraxacum mongolicum extract against respiratory infection-causing bacterial strains in vitro and in neonatal rats. Methods: The in vitro antibacterial activity was assessed by micro-dilution method. Antioxidant activity was determined by ferric reducing antioxidant power (FRAP), nitro blue tetrazolium (NBT) and 2, 2diphenyl-1-picrylhydrazyl (DPPH) assays. In vivo antimicrobial activity was evaluated in neonatal rat model. Interleukin (IL)-2 (IL-2) and gamma interferon (IFN-γ) were estimated using enzyme-linked immunosorbent assay (ELISA). Results: The hydro-methanol extract of T. mongolicum contained high levels of phenolics and flavonoids, and exhibited strong antimicrobial activity against respiratory infection-causing bacterial species with MICs of 25-100 µg/ml, and MBCs of 55-215 µg/ml. The highest and lowest antimicrobial activities were observed against Streptococcus pneumonia and Haemophilus influenza, respectively. The extract at doses of 25 and 50 mg/kg exerted protective effects against Streptococcus pneumoniainfected neonatal rats by boosting their Th1 immunity. It enhanced the production of interleukin (IL)-2, concomitant with decreased production of interferon (IFN)-γ in neonatal rats. The extract contained isoetin, hesperidin, naringenin, kaempferol, sinapinic and gallic acid. Conclusion: These results suggest that the hydro-methanolic extract of Taraxacum mongolicum and its constituents can be potentially developed for use in the management of respiratory bacterial infections.
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