陈建国
离子通道与受体药理学、突触可塑性与神经药理学
个性化签名
- 姓名:陈建国
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学术头衔:
博士生导师, 优秀教师/优秀教育工作者, 国家杰出青年科学基金获得者
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学科领域:
药物化学
- 研究兴趣:离子通道与受体药理学、突触可塑性与神经药理学
陈建国: 德国海德堡(Heidelberg)大学博士,美国爱荷华(Iowa)大学博士后,中国“国家杰出青年基金”获得者。德国凯撒斯劳滕(Kaiserslautern)大学、香港科技大学高级访问学者。现任华中科技大学特聘教授、同济医学院药理学系教授、博士生导师、系主任。兼任湖北省药理学会理事长、中国药理学会理事、心血管药理专业委员会委员、中国生物物理学会神经生物物理专业委员会常委、美国神经科学学会会员、国际杂志Journal of Cardiovascular Pharmacology和Acta Pharmacologica Sinica特约审稿人,全国医药院校五年制、八年制规划教材《药理学》、八年制精品教材《药理学》编委,全国“专升本”规划教材《护理药理学》副主编,《新编实用药物学》、《离子通道药理学》编委、《现代神经科学实验技术》编译委。研究领域主要集中于离子通道与受体药理学、突触可塑性与神经药理学。近年研究成绩主要包括: 发现代谢型谷氨酸受体参与胶质细胞间对话、脊髓背角疼痛调制的机制;发现自由基调节电压依赖性钾通道、钙依赖性钾通道、P/Q-型钙通道电流的作用靶点;首次报道可卡因转录相关肽介入可卡因成瘾的作用机制;最近的研究发现酸敏感通道和肌营养不良蛋白聚糖参与海马内突触长时增强和脑内学习记忆过程。近年来在“J. Neurosci.”、“Neuron”(封面文章)和“Nature”、“Neuropharmacology”等国际著名学术期刊发表论文20多篇。作为负责人,现承担有国家杰出青年基金、国家自然科学基金面上项目、中-港合作NSFC-RGC联合研究项目、科技部重大基础研究专项基金项目。获得“教育部优秀青年教师资助计划”资助,入选“湖北省新世纪高层次人才工程”。
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1542
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成果数
15
陈建国, Zhang-Jin Zhang a, *, Xiao-Long Jiang a, Steven E. Zhang , Christopher J. Hougha, He Li a, Jian-Guo Chen b, Xue-Chu Zhen b, c
Neuroscience Letters xxx(2005)xxx-xxx,-0001,():
-1年11月30日
While the benzazepine SKF83959 elicits classical behavioral responses associated with dopamine D1 receptors, it also acts as a D1 receptor antagonist biochemically. The paradoxical properties of this agent remain an enigma. In the present study, we sought to determine the behavioral effects of SKF83959 in the rat acoustic startle reflex test. Systemic administration of SKF83959 produced a dose-related increase in the startle amplitude with a stimulus of 105dB, and a significant group difference was observed between animals treated with 1mg/kg SKF83959 and vehicle controls. SKF83959 also significantly reduced the latency to startle response to stimuli of 95dB and 105dB in a dose-dependent manner. However, unlike classical dopamine D1-like receptor agonists, SKF83959 failed to disrupt prepulse inhibition (PPI) of either the startle amplitude or the latency to startle response; rather, the agent dose-dependently increased the PPI latency to startle response of 105dB stimulus. These results suggest that the behavioral effects of SKF83959 in the rat acoustic startle reflex paradigm are paradoxical, and these paradoxical effects may be associated with its distinct pharmacological properties.
SKF83959, Dopamine D1-like receptor, Agonist, Acoustic startle reflex, Rat
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【期刊论文】Sustained potentiation by substance P of NMDA-activated current in rat primary sensory neurons
陈建国, Zi-Zhen Wu a, Bing-Cai Guan a, Zhi-Wang Li a, *, Qing Yang b, Chang-Jin Liu c, Jian-Guo Chen d
Brain Research 1010(2004)117-126,-0001,():
-1年11月30日
This study aimed to explore the modulatory effect of substance P (SP) on the current response mediated by N-methyl-D-aspartate (NMDA) receptor in rat primary sensory neurons and its time course using whole-cell patch clamp technique. The majority of neurons (179/213, 84.0%) examined were sensitive to NMDA (0.1-1000μM) with an inward current, and a proportion of the NMDA-sensitive neurons also responded to SP (78/98, 80.0%) with an inward current. Pretreatment with SP potenti ated the NMDA-activated current (INMDA) in a non-competitive manner, which is shown in that SP shifted the concentration-response curve for NMDA upwards compared with the control; the maximal value of INMDA increased fourfold, while the EC50 values for both curves were very close (28vs. 30μM). Furthermore, this potentiating effect was time-dependent: the amplitude of INMDA reached its maximum 20min after SP preapplication, and thereafter maintained a steady level of about 2-3 times its control for 2 or even 3h. This sustained potentiation by SP of INMDA could be blocked by extracellular application of WIN51708, a selective non-peptide antagonist of NK-1 receptor; and abolished by intracellular application of either BAPTA, or H-7, or KN-93. Though NMDA applied alone also induced a short-term (less than 20min) self-potentiation of INMDA, it could be abolished by intracellular dialysis of BAPTA or KN-93 completely. As is known, the cell body of dorsal root ganglion (DRG) neurons is generally used as an accessible model for studying the characteristics of the membrane of primary afferent terminals in the dorsal horn of spinal cord. Therefore, these results may offer a clue to the explanation of the symptoms of chronic pain.
Substance P, NMDA-activated current, Sustained potentiation, Primary sensory neuron, Whole-cell patch clamp, Intracellular dialysis, Rat
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陈建国, Lindsey Ciali Santarelli, Jianguo Chen, Stefan H. Heinemann, and Toshinori Hoshi
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-1年11月30日
Oxidative stress may alter the functions of many proteins including the Slo1 large conductance calcium-activated potassium channel (BK Ca). Previous results demonstrated that in the virtual absence of Ca2+, the oxidant chloramine-T (Ch-T), without the involvement of cysteine oxidation, increases the open probability and slows the deactivation of BK Ca channels formed by human Slo1 (hSlo1) a subunits alone. Because native BK Ca channel complexes may include the auxiliary subunit β1, we investigated whether β1 influences the oxidative regulation of hSlo1. Oxidation by Ch-T with β1 present shifted the half-activation voltage much further in the hyperpolarizing direction (-75mV) as compared with that with alone (-30mV). This shift was eliminated in the presence of high [Ca2+]i but the increase in open probability in the virtual absence of Ca2+ remained significant at physiologically relevant voltages. Furthermore, the slowing of channel deactivation after oxidation was even more dramatic in the presence of β1. Oxidation of cysteine and methionine residues within β1 was not involved in these potentiated effects because expression of mutant β1 subunits lacking cysteine or methionine residues produced results similar to those with wild-type β1. Unlike the results with alone, oxidation by Ch-T caused a ignificant acceleration of channel activation only when β1 was present. The β1 M177 mutation disrupted normal channel activation and prevented the Ch-T-induced acceleration of activation. Overall, the functional effects of oxidation of the hSlo1 pore-forming subunit are greatly amplified by the presence of β1, which leads to the additional increase in channel open probability and the slowing of deactivation. Furthermore, M177 within β1 is a critical structural determinant of channel activation and oxidative sensitivity. Together, the oxidized BKCa channel complex with β1 has a considerable chance of being open within the physiological voltage range even at low [Ca2+] i.
BK Ca • hslo • chloramine-T • methionine • cysteine
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【期刊论文】Characterization of Acid-sensing Ion Channels in Dorsal Horn Neurons of Rat Spinal Cord*
陈建国, Long-Jun Wu ‡, §, Bo Duan ‡, Yi-De Mei§, Jun Gao ‡, Jian-Guo Chen ¶, Min Zhuo, Lin Xu *, *, Mian Wu §, and Tian-Le Xu ‡, ‡
Vol.279, No.42, Issue of October 15, pp.43716-43724, 2004,-0001,():
-1年11月30日
Acid-sensing ion channels (ASICs) are ligand-gated cation channels activated by extracellular protons. In periphery, they contribute to sensory transmission, including that of nociception and pain. Here we characterized ASIC-like currents in dorsal horn neurons of the rat spinal cord and their functional modulation in pathological conditions. Reverse transcriptase-nested PCR and Western blotting showed that three ASIC isoforms, ASIC1a, ASIC2a, and ASIC2b, are expressed at a high level in dorsal horn neurons. Electrophysiological and pharmacological properties of the proton-gated currents suggest that homomeric ASIC1a and/or heteromeric ASIC1a 2b channels are responsible for the proton-induced currents in the majority of dorsal horn neurons. Acidification-induced action potentials in these neurons were compatible in a pH-dependent manner with the pH dependence of ASIC-like current. Furthermore, peripheral complete Freund's adjuvant-induced inflammation resulted in increased expression of both ASIC1a and ASIC2a in dorsal horn. These results support the idea that the ASICs of dorsal horn neurons participate in central sensory transmission/modulation under physiological conditions and may play important roles in inflammation-related persistent pain.
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【期刊论文】Substance P potentiates 5-HT3 receptor-mediated current in rat trigeminal ganglion neurons
陈建国, Wang-Ping Hu a, b, Xing-Hong You a, c, Bing-Cai Guan a, Li-Qiang Ru a, Jian-Guo Chen d, , Zhi-Wang Li a, *∗
Neuroscience Letters 365(2004)147-152,-0001,():
-1年11月30日
The present study aimed to investigate the interaction between the coexistent SP receptor and 5-HT3 receptor in trigeminal ganglion (TG) neurons using whole-cell patch clamp technique. The majority of the neurons examined responded to 5-HT with an inward current (I5-HT) (78.2%, 79/101) that could be blocked by 5-HT3 receptor antagonist, ICS-205, 930. The I5-HT was potentiated by preapplication of SP (10−10 to 10−8M) in most 5-HT-sensitive cells (78.5%, 62/79). Coapplication of SP and GR-82334, antagonist of NK1 receptor, had no enhancing effect on I5-HT. The concentration-response curves for 5-HT with and without SP preapplication show that: (1) the threshold 5-HT concentrations with and without SP preapplication are basically the same, while SP preapplication increased the maximal value of I5-HT by 38.0% of its control; (2) the EC50 values of the curves with and without SP pretreatment are very close, i.e. 1.89×10−5M and 2.08×10−5M (P>0.1; n=9), respectively. Intracellular dialysis of GDP-S, a non-hydrolyzable GDP analog, and GF-109203X, a selective protein kinase C inhibitor, removed the SP potentiation of I5-HT. These results may offer a clue understanding the mechanism underlying the generation and/or regulation of peripheral pain caused by tissue damage inflammation, etc.
Substance P, Potentiation, 5-HT3 receptor, Current, Trigeminal ganglion, Rat
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陈建国, Wang-Ping Hu a, b, c, Bing-Cai Guan b, Li-Qiang Ru b, Jian-Guo Chen a, d, , Zhi-Wang Li a, *
Neuropharmacology 47(2004)833-840,-0001,():
-1年11月30日
5-HT receptor subtypes are widely expressed in primary sensory neurons, yet so far little is known about the interaction among them. This study aimed to investigate whether the activation of 5-HT2 and 5-HT1 receptors could modulate 5-HT3 receptor mediated current in rat trigeminal ganglion (TG) neurons using whole-cell patch clamp technique. The majority of TG neurons examined responded to 5-HT (10-7-10-3M) with a fast activating and rapid desensitizing inward current (77.2%, 71/92). This 5-HT activated current (I5-HT) was blocked by ICS 205-930 and mimicked by 2-methyl-5-HT, indicating that it was mediated by 5-HT3 receptor. With a-methyl-5-HT applied prior to 5-HT application, I5-HT was otentiated in a concentration-dependent manner, with the maximal modulatory effect at 10-9 M of a-methyl-5-HT. The concentration-response curve for I5-HT pretreated with amethyl-5-HT shifts upwards compared with that for I5-HT without a-methyl-5-HT pretreatment, the maximal I5-HT value having increased by (60.3
5-HT3 receptor, 5-HT2 receptor, Modulation, Whole-cell patch clamp, Trigeminal ganglion, Rat
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陈建国, JIANGUO CHEN, * HEATHER DAGGETT, * MICHEL DE WAARD, †, S. H. HEINEMANN, ‡ and TOSHINORI HOSHI *
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-1年11月30日
P/Q-type Ca2+ channels, which are postulated to play major roles in synaptic transmission, are regulated in a variety of ways. Ca2+ currents through P/Q-type Ca2+ channels (Cav2.1/β1a/a2δ) heterologously expressed in mammalian cells were recorded using the whole-cell patch clamp method. The oxidant H2O2 increased the current amplitude and the effect was reversed by the reducing agent dithiothreitol (DTT). The stimulatory effect of H2O2 on the Ca2+ current was mimicked by the NO donors, SNAP, and diethylamine NONOate, and reversed by the reducing agent DTT. The presence of a soluble guanylate cyclase inhibitor did not abolish the ability of SNAP to increase the Ca2+ current. Adenovirus-mediated overexpression of nitric oxide synthase in combination with application of the Ca2+ ionophore A23187 also increased the Ca2+ current amplitude and the effect was again reversed by DTT. The NOS inhibitor L-NAME abolished the stimulatory effect of A23187, and A23187 did not change the Ca2+ currents in the cells treated with control adenovirus particles. The time course of the decline of the Ca2+ current, but not of the Ba2+ current, in response to repeated epolarization was markedly slowed by adenovirus-mediated overexpression of nitric oxide synthase. The results demonstrate that nitric oxide enhances the channel activity by promoting oxidation and suggest that Ca2+, nitric oxide synthase, and nitric oxide could constitute a positive feedback loop for regulation of voltage-gated P/Q-type Ca2+ channels.
Oxidation,, Reactive oxygen species,, Nitric oxide,, Channel gating,, Calcium channel,, Free radicals
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【期刊论文】The Acid-Activated Ion Channel ASIC Contributes to Synaptic Plasticity, Learning, and Memory
陈建国, John A. Wemmie, , Jianguo Chen, Candice C. Askwith, Alesia M. Hruska-Hageman, Margaret P. Price, Brian C. Nolan, Patrick G. Yoder, Ejvis Lamani, Toshinori Hoshi, John H. Freeman, Jr., and Michael J. Welsh
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-1年11月30日
Many central neurons possess large acid-activated inhibicurrents, yet their molecular identity is unknown. We found that eliminating the acid sensing ion channel (ASIC) abolished H+-gated currents in hippocampal neurons. Neuronal H+-gated currents and transient acidification are proposed to play a role in synaptic centransmission. Investigating this possibility, we found ASIC in hippocampus, in synaptosomes, and in den-drites localized at synapses. Moreover, loss of ASIC nerimpaired hippocampal long-term potentiation. ASIC null mice had reduced excitatory postsynaptic poten-tials and NMDA receptor activation during high-fre-quency stimulation. Consistent with these findings, null mice displayed defective spatial learning and eye-blink conditioning. These results identify ASIC as a key component of acid-activated currents and implicate these currents in processes underlying synaptic plas-ticity, learning, and memory.
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【期刊论文】Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy
陈建国, Steven A. Moore *, Fumiaki Saito †, Jianguo Chen ‡, Daniel E. Michele †, Michael D. Henry †, Albee Messing §, Ronald D. Cohn † Susan E. Ross-Barta *, Steve Westra *, Roger A. Williamsonk, Toshinori Hoshi ‡, & Kevin P. Campbell †
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-1年11月30日
Fukuyama congenital muscular dystrophy (FCMD), muscle-eye-brain disease (MEB), and Walker-Warburg syndrome are congenital muscular dystrophies (CMDs) with associated developmental brain defects1-4. Mutations reported in genes of FCMD2 and MEB5 patients suggest that the genes may be involved in protein glycosylation. Dystroglycan is a highly glycosylated component of the muscle dystrophin-glycoprotein complex6 that is also expressed in brain, where its function is unknown7. Here we show that brain-selective deletion of dystroglycan in mice is sufficient to cause CMD-like brain malformations, including disarray of cerebral cortical layering, fusion of cerebral hemispheres and cerebellar folia, and aberrant migration of granule cells. Dystroglycan-null brain loses its high-affinity binding to the extracellular matrix protein laminin, and shows discontinuities in the pial surface basal lamina (glia limitans) that probably underlie the neuronal migration errors. urthermore, mutant mice have severely blunted hippocampal longterm potentiation with electrophysiologic characterization indicating that dystroglycan might have a postsynaptic role in learning and memory. Our data strongly support the hypothesis that defects in dystroglycan are central to the pathogenesis of structural and functional brain abnormalities seen in CMD.
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陈建国, Olena Yermolaieva, Jianguo Chen, Pastor R. Couceyro, and Toshinori Hoshi
The Journal of Neuroscience, October 1, 2001, 21 (19): 7474-7480,-0001,():
-1年11月30日
Administration of cocaine and amphetamine increases cocaine- and amphetamine-regulated transcript (CART) expression in the rat striatum (Douglass et al., 1995). CART mRNA is highly expressed in different parts of the human and rat brain, including hippocampus (Douglass et al., 1995; Couceyro et al., 1997; Kuhar and Yoho, 1999; Hurd and Fagergren, 2000). The presence of CART peptide 55-102 immunoreactivity in dense core vesicles of axon terminals suggests that the peptide may be released and may act as a neuromodulator (Smith et al., 1997) to induce neurophysiological and behavioral effects. Little is known, however, about CART peptide-responsive cells, receptor(s), or intracellular signaling mechanisms that mediate CART peptide action. Here we show that CART peptide 55-102 inhibits voltage-dependent intracellular Ca+ signaling and attenuates cocaine enhancement of depolarization-induced Ca+ influx in rat hippocampal neurons. The inhibitory effect of CART peptide 55-102 on Ca+ signaling is likely mediated by an inhibition of L-type voltage-gated Ca+ channel activity via a G-protein-dependent pathway. These results indicate that voltage-gated Ca+ channels in hippocampal neurons are targets for CART peptide 55-102 and suggest that CART peptides may be important in physiology and behavior mediated by the hippocampus, such as certain forms of learning and memory.
hippocampus, neuropeptide, cocaine, CART, calcium, voltage-gated calcium channels
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