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A v-SNARE participates in synaptic vesicle formation mediated by the AP3 adaptor complex

NATURE NEUROSCIENCE 1998年第7期1卷 551-556页

作者： Salem, N Faúndez, V Horng, JT Kelly, RB Univ Calif San Francisco Dept Biochem & Biophys San Francisco CA 94143 USA Univ Calif San Francisco Hormone Res Inst San Francisco CA 94143 USA

Reconstitution of synaptic vesicle formation in vitro has revealed a pathway of synaptic vesicle biogenesis from endosomes that requires the heterotetrameric adaptor complex AP3. Because synaptic vesicles have a distinct protein composition, the AP3 complex should selectively recognize some or all of the synaptic vesicle proteins. Here we show that one element of this recognition process is the v-SNARE, VAMP-2, because tetanus toxin, which cleaves VAMP-2, inhibited the formation of synaptic vesicles and their coating with AP3 in vitro. Mutant tetanus toxin and botulinum toxins, which cleave t-SNAREs, did not inhibit synaptic vesicle production. AP3-containing complexes isolated from coated vesicles could be immunoprecipitated by a VAMP-2 antibody. These data imply that AP3 recognizes a component of the fusion machinery, which may prevent the production of inert synaptic vesicles.

关键词：衔接蛋白复合物3 衔接蛋白复合物α亚单位衔接蛋白质类膜泡运输肉毒毒素类/药理学有被小泡/药物作用有被小泡/生理学基因打靶膜蛋白质类/拮抗剂和抑制剂膜蛋白质类/遗传学膜蛋白质类/生理学单体网格蛋白装配蛋白质类 PC12细胞 R-SNARE蛋白质类突触小泡/药物作用突触小泡/生理学破伤风毒素/药理学动物大鼠

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Inhibition of brain vesicular monoamine transporter (VMAT2) enhances 1-methyl-4-phenylpyridinium neurotoxicity in vivo in rat striata

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期293卷 336-342页

作者： Staal, RGW Sonsalla, PK Univ Med & Dent New Jersey Robert Wood Johnson Med Sch Dept Neurol Piscataway NJ 08854 USA

Dopamine neurons from various animal species differ in sensitivity to the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+). Compared with striatal vesicles isolated from mice, those from rats have a higher density of the brain vesicular monoamine transporter (VMAT2) and a greater ability to sequester MPP+, suggesting a larger storage capacity for MPP+ in rat vesicles. In the present study, we examined whether striatal VMAT2-containing vesicles might provide protection against the neurotoxic effects of MPP+ in vivo. Dose-response curves for striatally infused MPP+ were determined in animals pretreated with or without a VMAT2 inhibitor. Ro 4-1284 administration (10 mg/kg i.p.;VMAT2 inhibitor) produced a 5-fold leftward shift in the MPP+ dose-response curve and a significant lowering of the EC50 concentration for MPP+-induced damage. These findings provide evidence for a substantial accumulation of MPP+ in VMAT2-containing vesicles in vivo in the rat striatum and support the hypothesis that MPP+ sequestration in vesicles can provide protection against its toxic actions. In mice, VMAT2 inhibition did not reliably enhance toxicity produced by a striatal infusion of MPP+ or by systemic administration of MPTP. These data suggest that vesicular sequestration of MPP+ may be of less importance in mice than in rats as relates to protection from the toxin. The present results also reveal that although VMAT2 inhibition enhanced striatal MPP+ toxicity in the rat, the potency of MPP+ in the rat striatum was less than that in mouse striatum. This implies that there are other factors that either exacerbate MPP+ toxicity in the mouse or attenuate MPP+ toxicity in rats.

关键词：脑化学/药物作用剂量效应关系药物膜糖蛋白类/拮抗剂和抑制剂膜转运蛋白质类微透析新纹状体/药物作用新纹状体/代谢神经肽类神经毒素类/毒性神经递质药/拮抗剂和抑制剂大鼠 Sprague-Dawley 种特异性突触小泡/药物作用突触小泡/代谢时间因素囊泡生物胺转运蛋白质类囊泡单胺转运蛋白质类动物男(雄)性小鼠大鼠

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In vitro studies of striatal vesicles containing the vesicular monoamine transporter (VMAT2): Rat versus mouse differences in sequestration of 1-methyl-4-phenylpyridinium

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期293卷 329-335页

作者： Staal, RGW Hogan, KA Liang, CL German, DC Sonsalla, PK Univ Med & Dent New Jersey Robert Wood Johnson Med Sch Dept Neurol Piscataway NJ 08854 USA Univ Texas SW Med Ctr Dept Psychiat Dallas TX USA

Significant differences exist in the sensitivity of mice and rats to the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that cannot be explained by differences in exposure to or uptake of 1-methyl-4-phenylpyridinium (MPP+) into dopamine (DA) neurons. MPP+ is also a substrate for the brain vesicular monoamine transporter (VMAT2), and sequestration into synaptic vesicles may be one mechanism of protection against MPP+ toxicity. A greater sequestration of MPP+ into vesicles of DA neurons in rats versus mice could explain the lower vulnerability of DA neurons in the rat to MPP+ toxicity. To test this hypothesis, the kinetics of uptake for [H-3]MPP+ and [H-3]DA as well as [H-3]dihydrotetrabenazine binding to VMAT2 were compared in vesicles isolated from the striata of rats and mice. The K-m value of [H-3]MPP+ transport was similar in the two species. In contrast, the maximal transport rate (V-max) was 2-fold greater in vesicles from rats than in those from mice. Likewise, the K-m value for [H-3]DA transport was similar in both preparations, but the V-max value was 2-fold greater in rat than in mouse vesicles. The B-max value for [H-3]dihydrotetrabenazine binding was also 2-fold greater in striatal vesicles from rats than in those from mice. Electron micrographs demonstrated that vesicles isolated from rats and mice were approximately the same size. Based on these observations, we propose that striatal vesicles from rats have more VMAT2 than vesicles from mice and that this species difference in VMAT2 density may help explain the reduced vulnerability of rat DA neurons to MPP+ neurotoxicity.

关键词： 1-甲基-4-苯基吡啶/代谢可卡因/类似物和衍生物可卡因/代谢多巴胺药/代谢多巴胺摄取抑制剂/代谢指示剂和试剂动力学膜糖蛋白类/代谢膜转运蛋白质类显微镜检查电子新纹状体/药物作用新纹状体/代谢新纹状体/超微结构神经肽类神经毒素类/代谢神经递质药/代谢大鼠 Sprague-Dawley 种特异性突触小泡/药物作用突触小泡/代谢突触小泡/超微结构囊泡生物胺转运蛋白质类囊泡单胺转运蛋白质类动物男(雄)性小鼠大鼠

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SYNAPTOSOMES CONTAINING LARGE AGRANULAR VESICLES ISOLATED FROM DEVELOPING RAT-BRAIN

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ACTA PHYSIOLOGICA SCANDINAVICA 1975年第3期94卷 393-397页

作者： KANERVA, L HERVONEN, A TISSARI, AH UNIV HELSINKI DEPT ANATHELSINKIFINLAND UNIV HELSINKI DEPT PHARMACOLHELSINKIFINLAND UNIV TAMPERE INST BIOMED SCITAMPEREFINLAND

Using the subcellular fractionation technique the fine structure of the isolated nerve endings (synaptosomes) from the hemispheres and brain stem of the 1-day old and adult rat was examined. In the synaptosomal fractions of the brain of 1-day old rats we observed a new type of nerve endings containing predominantly large agranular vesicles about 1,000 A in diameter. After incubation with alpha-methylnoradrenaline or 5-hydroxydopamine these vesicles remained agranular. It is assumed that the new type of large vesicles represent developing synaptic vesicles.

关键词：年龄因素动物新生脑/生长和发育脑干/生长和发育羟基多巴胺类/药理学甲基去甲肾上腺素/药理学亚细胞部分突触小泡/药物作用突触小泡/超微结构突触体/超微结构动物大鼠

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VESICULAR NORADRENALINE IN NERVE-TERMINALS OF RAT-HEART FOLLOWING INHIBITION OF MONOAMINE-OXIDASE AND ADMINISTRATION OF NORADRENALINE

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NEUROSCIENCE 1976年第2期1卷 113-116页

作者： FILLENZ, M HOWE, PRC WEST, DP UNIV OXFORD PHYSIOL LABOXFORDENGLAND

The administration of either exogenous noradrenaline or a monoamine oxidase inhibitor causes a rise in the noradrenaline content of vesicles in sympathetic nerve terminals of rat heart ventricle. The additional noradrenaline is firmly bound. The capacity of vesicles for storing noradrenaline shows a saturation value and the vesicles in the nerve terminals of the heart have a noradrenaline content which is normally below this value.

关键词：多巴胺/药理学心脏/药物作用心脏/神经支配单胺氧化酶抑制剂去甲肾上腺素/代谢去甲肾上腺素/药理学突触小泡/药物作用突触小泡/酶学突触小泡/代谢时间因素反苯环丙铵/药理学动物男(雄)性大鼠

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Cyclosporine A-induced hypertension involves synapsin in renal sensory nerve endings

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第17期97卷 9765-9770页

作者： Zhang, WG Li, JL Hosaka, M Lanz, R Shelton, JM Albright, GM Richardson, JA Südhof, TC Victor, RG Univ Texas SW Med Ctr Dept Internal Med Dallas TX 75390 USA Univ Texas SW Med Ctr Dept Mol Genet Dallas TX 75390 USA Univ Texas SW Med Ctr Ctr Basic Neurosci Dallas TX 75390 USA Univ Texas SW Med Ctr Dept Pathol Dallas TX 75390 USA Univ Texas SW Med Ctr Howard Hughes Med Inst Dallas TX 75390 USA

The calcineurin inhibitor cyclosporine A (CsA) has emerged as a major cause of secondary hypertension in humans, but the underlying pathogenetic mechanisms have remained enigmatic. Synapsins are a family of synaptic vesicle phosphoproteins that are essential for normal regulation of neurotransmitter release at synapses. In addition to synaptic vesicles, synapsins and other vesicle proteins are found on microvesicles in sensory nerve endings in peripheral tissues. However, the functions of the sensory microvesicles in general, and of synapsins in particular, are unknown. We now demonstrate in a mouse model that CsA raises blood pressure by stimulating renal sensory nerve endings that contain synapsin-positive microvesicles. In knockout mice lacking synapsin I and II, sensory nerve endings are normally developed but not stimulated by CsA whereas a control stimulus, capsaicin, is fully active. The reflex activation of efferent sympathetic nerve activity and the increase in blood pressure by CsA seen in control are greatly attenuated in synapsin-deficient mice. These results provide a mechanistic explanation for CsA-induced acute hypertension and suggest that synapsins could serve as a drug target in this refractory condition. Furthermore, these data establish evidence that synapsin-containing sensory microvesicles perform an essential role in sensory transduction and suggest a role for synapsin phosphorylation in this process.

关键词：传入通路/药物作用传入通路/代谢血压/药物作用辣椒辣素/药理学环孢菌素/代谢环孢菌素/药理学疾病模型动物高血压/化学诱导高血压/代谢免疫组织化学嗜免疫剂/代谢肾/药物作用肾/神经支配配体小鼠近交C57BL 小鼠基因敲除神经末梢/药物作用神经末梢/代谢神经元传入/药物作用神经元传入/代谢 P物质/分析交感神经系统/细胞学交感神经系统/药物作用交感神经系统/代谢突触蛋白类/缺乏突触蛋白类/遗传学突触蛋白类/代谢突触小泡/药物作用突触小泡/代谢 rab3AGTP结合蛋白质/分析动物女(雌)性男(雄)性小鼠

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EFFECT OF ASCORBIC-ACID ON RELEASE OF ACETYLCHOLINE FROM SYNAPTIC VESICLES PREPARED FROM DIFFERENT SPECIES OF ANIMALS AND RELEASE OF NORADRENALINE FROM SYNAPTIC VESICLES OF RAT-BRAIN

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LIFE SCIENCES 1979年第10期24卷 911-916页

作者： KUO, CH HATA, F YOSHIDA, H YAMATODANI, A WADA, H OSAKA UNIV SCH MED DEPT PHARMACOL 2 OSAKA 530 JAPAN

Low concentrations of L-ascorbic acid caused release of acetylcholine from isolated synaptic vesicles (rat, guinea-pig and rabbit) in the presence of 2 mM ATP, 2 mM MgCl2 and 10-5 M CaCl. The half maximum effect was obtained with about 2-2.5 .mu.M L-ascorbic acid, and the effect was inhibited by addition of 1 mM EGTA [ethylene glycol-bis(.beta.-aminoethyl ether)N,N,N'',N''-tetraacetic acid]. The release of noradrenaline [norepinephrine] from rat synaptic vesicles was also enhanced by L-ascorbic acid, but the concentration for half maximal stimulation was about 20 .mu.M, indicating that noradrenaline release was less sensitive to L-ascorbic acid than acetylcholine release. The physiological function of L-ascorbic acid in the brain is discussed in relation to release of transmitters.

关键词：乙酰胆碱/代谢抗坏血酸/拮抗剂和抑制剂抗坏血酸/药理学脑/药物作用脑/代谢依他酸/药理学去甲肾上腺素/代谢种特异性突触小泡/药物作用突触小泡/代谢时间因素动物豚鼠兔大鼠

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Depression of synaptic efficacy in high- and low-output Drosophila neuromuscular junctions by the molting hormone (20-HE)

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JOURNAL OF NEUROPHYSIOLOGY 1999年第2期81卷 788-794页

作者： Ruffner, ME Cromarty, SI Cooper, RL Univ Kentucky Thomas Hunt Morgan Sch Biol Sci 100 Nerve Muscle Grp Lexington KY 40506 USA

The molt-related steroid hormone, 20-hydroxyecdysone (20-HE), was applied to muscles 6 and 7 of third instar larval of Drosophila melanogaster neuromuscular junction preparations to examine if rapid, nongenomic responses could be observed as was shown recently to occur in crustacean neuromuscular junctions. At a dose of 10 mu M, the excitatory junction potentials were reduced in amplitude within minutes. To elucidate the site of action of the hormone, focal-macropatch recordings of synaptic currents were obtained over the neuromuscular junctions. The results showed that the high-output (Is) and the low-output (Ib) motor nerve terminals, which innervate muscles 6 and 7, released fewer synaptic vesicles for each stimulation while exposed to 20-HE. Because the size and shape of synaptic currents from spontaneous releases did not change, the effects of the 20-HE are presynaptic. The rapid effects of this hormone may account in part for the quiescent behavior associated with molts among insects and crustaceans.

关键词：黑腹果蝇蜕皮甾酮/药理学兴奋性突触后电位/药物作用幼虫/生理学运动神经元/药物作用运动神经元/生理学肌/神经支配神经肌肉接头/药物作用神经肌肉接头/生理学膜片钳术突触传递/药物作用突触传递/生理学突触小泡/药物作用时间因素动物

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Empty synaptic vesicles recycle and undergo exocytosis at vesamicol-treated motor nerve terminals

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JOURNAL OF NEUROPHYSIOLOGY 1999年第6期81卷 2696-2700页

作者： Parsons, RL Calupca, MA Merriam, LA Prior, C Univ Vermont Coll Med Dept Anat & Neurobiol Burlington VT 05405 USA Univ Strathclyde Dept Physiol & Pharmacol Strathclyde Inst Biomed Sci Glasgow G4 0NR Lanark Scotland

Empty synaptic vesicles recycle and undergo exocytosis at vesamicol-treated motor nerve terminals. J. Neurophysiol,. 81: 2696-2700, 1999. We investigated whether recycled cholinergic synaptic vesicles, which were not refilled with ACh, would join other synaptic vesicles in the readily releasable store near active zones, dock, and continue to undergo exocytosis during prolonged stimulation. Snake nerve-muscle preparations were treated with 5 mu M vesamicol to inhibit the vesicular ACh transporter and then were exposed to an elevated potassium solution, 35 mM potassium propionate (35 KP), to release all preformed quanta of ACh. At vesamicol-treated endplates, miniature endplate current (MEPC) frequency increased initially from 0.4 to >300 s(-1) in 35 KP but then declined to <1 s(-1) by 90 min. The decrease in frequency was not accompanied by a decrease in MEPC average amplitude, Nerve terminals accumulated the activity-dependent dye FM1-43 when exposed to the dye for the final 6 min of a 120-min exposure to 35 KP. Thus synaptic membrane endocytosis continued at a high rate, although MEPCs occurred infrequently. After a 120-min exposure in 35 KP, nerve terminals accumulated FM1-43 and then destained, confirming that exocytosis also still occurred at a high rate. These results demonstrate that recycled cholinergic synaptic vesicles that were not refilled with ACh continued to dock and undergo exocytosis after membrane retrieval. Thus transport of ACh into recycled cholinergic vesicles is not a requirement for repeated cycles of exocytosis and retrieval of synaptic vesicle membrane during prolonged stimulation of motor nerve terminals.

关键词：乙酰胆碱/代谢载体蛋白质类/拮抗剂和抑制剂游蛇科电刺激胞吐作用荧光染料膜转运蛋白质类运动神经肌肉终板/药物作用运动神经肌肉终板/生理学运动神经元/药物作用神经末梢/药物作用哌啶类/药理学吡啶鎓化合物季胺类化合物突触膜/药物作用突触膜/生理学突触小泡/药物作用突触小泡/代谢囊泡乙酰胆碱转运蛋白质类膜泡运输蛋白质类动物

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Ca²⁺-dependent regulation of synaptic SNARE complex assembly via a calmodulin- and phospholipid-binding domain of synaptobrevin

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第17期97卷 9695-9700页

作者： Quetglas, S Leveque, C Miquelis, R Sato, K Seagar, M Univ Mediterrannee Inst Natl Sante F-13916 Marseille 20 France Univ Mediterrannee Rech Med Unit 464 F-13916 Marseille France Univ Mediterrannee CNRS UMR 6560 F-13916 Marseille 20 France Univ Mediterrannee Fac Med Secteur Nord Inst Fed Rech Jean Roche Unite Methodol Interact Mol F-13916 Marseille 20 France Mitsubishi Kasei Inst Life Sci Machida Tokyo 1948511 Japan

Synaptic core complex formation is an essential step in exocytosis, and assembly into a superhelical structure may drive synaptic vesicle fusion. To ascertain how Ca2+ could regulate this process, we examined calmodulin binding to recombinant core complex components. Surface plasmon resonance and pull-down assays revealed Ca2+-dependent calmodulin binding (K-d = 500 nM) to glutathione S-transferase fusion proteins containing synaptobrevin (VAMP 2) domains but not to syntaxin 1 or synaptosomal-associated protein of 25 kDa (SNAP-25). Deletion mutations, tetanus toxin cleavage, and peptide synthesis localized the calmodulin-binding domain to VAMP(77-94), immediately C-terminal to the tetanus toxin cleavage site (Q(76-F77)) In isolated synaptic vesicles, Ca2+/calmodulin protected native membrane-inserted VAMP from proteolysis by tetanus toxin, Assembly of a S-35-SNAP-25, syntaxin I GST-VAMP(1-96) complex was inhibited by Ca2+/calmodulin, but assembly did not mask subsequent accessibility of the calmodulin-binding domain. The same domain contains a predicted phospholipid interaction site. SPR revealed calcium-independent interactions between VAMP77-94 and liposomes containing phosphatidylserine, which blocked calmodulin binding. Circular dichroism spectroscopy demonstrated that the calmodulin/phospholipid-binding peptide displayed a significant increase in alpha-helical content in a hydrophobic: environment. These data provide insight into the mechanisms by which Ca2+ may regulate synaptic core complex assembly and protein interactions with membrane bilayers during exocytosis.

关键词：氨基酸序列抗原表面/化学抗原表面/遗传学抗原表面/代谢结合部位钙/代谢钙/药理学钙调蛋白/代谢钙调蛋白/药理学圆二色性胞吐作用脂质体/化学脂质体/药物作用脂质体/代谢膜蛋白质类/化学膜蛋白质类/遗传学膜蛋白质类/代谢分子序列数据神经组织蛋白质类/化学神经组织蛋白质类/遗传学神经组织蛋白质类/代谢磷脂酰丝氨酸类/代谢磷脂类/代谢蛋白质结合/药物作用蛋白质加工转译后/药物作用蛋白质结构二级 R-SNARE蛋白质类重组融合蛋白质类/化学重组融合蛋白质类/遗传学重组融合蛋白质类/代谢 SNARE蛋白质类序列比对表面等离激元突触小泡/药物作用突触小泡/代谢突触体相关蛋白质25 突触融合蛋白质1 破伤风毒素/药理学膜泡运输蛋白质类动物

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