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Organization and regulation of proteins at synapses (vol 11, pg 248, 1999)

CURRENT OPINION IN CELL BIOLOGY 1999年第3期11卷 407-408页

作者： Kim, JH Huganir, RL DepartmentofNeuroscience HowardHughesMedicalInstituteJohnsHopkinsUniversitySchoolofMedicineBaltimoreMD21205USA.

The organization and regulation of synaptic connections in the mammalian nervous system entail complicated and coordinated molecular and cellular processes. The unveiling of various protein-protein interactions and their functional consequences at synapses have led to a greater understanding of the process of synapse formation and the modulation of synaptic transmission. Recent studies indicate that the major excitatory neurotransmitter receptors in the brain, the glutamate receptors, are associated with many different molecules that are involved in the formation of elaborate synaptic cytoskeletal networks and signal transduction cascades. These complex protein networks may play critical roles in the regulation of neurotransmitter receptor function and the efficacy of synaptic transmission.

关键词：脑/生理学离子通道/生理学膜融合模型神经学神经组织蛋白质类/生理学神经元/生理学神经递质药/生理学受体神经递质/生理学信号传导/生理学突触/生理学突触/超微结构突触传递/生理学动物人类

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G-protein-independent signaling by G-protein-coupled receptors

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TRENDS IN NEUROSCIENCES 2000年第10期23卷 469-475页

作者： Heuss, C Gerber, U Univ Zurich Brain Res Inst CH-8057 Zurich Switzerland

Two classes of receptors transduce neurotransmitter signals: ionotropic receptors and heptahelical metabotropic receptors. Whereas the ionotropic receptors are structurally associated with a membrane channel, a mediating mechanism is necessary to functionally link metabotropic receptors with their respective effecters. According to the accepted paradigm, the first step in the metabotropic transduction process requires the activation of heterotrimeric G-proteins, An increasing number of observations, however, point to a novel mechanism through which neurotransmitters can initiate biochemical signals and modulate neuronal excitability, According to this mechanism metabotropic receptors induce responses by activating transduction systems that do not involve G-proteins.

关键词：基因表达调控异源三聚体GTP结合蛋白质类/生理学无脊椎动物/生理学 MAP激酶信号系统/药物作用模型神经学神经组织蛋白质类/生理学神经递质药/药理学受体蛋白质酪氨酸激酶类/生理学受体生长因子/生理学受体亲代谢性谷氨酸盐/药物作用受体亲代谢性谷氨酸盐/生理学受体神经递质/分类受体神经递质/药物作用受体神经递质/生理学信号传导/药物作用信号传导/生理学突触传递/药物作用突触传递/生理学转录激活脊椎动物/生理学 src族激酶类/生理学动物人类

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PROTECTION AGAINST ISCHEMIC HIPPOCAMPAL CA1 DAMAGE IN THE RAT WITH A NEW NON-NMDA ANTAGONIST, NBQX

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ACTA NEUROLOGICA SCANDINAVICA 1992年第1期86卷 45-49页

作者： DIEMER, NH JORGENSEN, MB JOHANSEN, FF SHEARDOWN, M HONORE, T NOVO NORDISK DIV CNSSOBORGDENMARK

Two glutamate antagonists were tested in a rat model of complete, transient cerebral ischemia. Six days after 10 min ischemia the mean loss of hippocampal CA1 pyramidal neurones was 73%. Administration of the AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid) antagonist NBQX (2,3-dihydro-6-nitro-7-sulfamoyl-benzo(F)quinoxaline) reduced the pyramidal neurone loss to 1%, 11% and 15%, when given before, immediately after or 1 h after ischemia, respectively. MK-801 (dizocilpine), a competitive NMDA antagonist gave no protection in this model. We suggest that the AMPA receptor transduction mechanisms are sensitized by ischemia and that the postischemic blockade of the main glutamatergic input to the CA1 cells with NBQX impairs the deleterious effect of "normal" postischemic excitatory transmission.

关键词：脑损害慢性/病理学脑缺血/病理学细胞计数海马/血液供给海马/病理学神经变性/药物作用神经变性/生理学神经元/药物作用神经元/病理学喹恶啉类/药理学大鼠近交系受体 AMPA 受体谷氨酸受体 N-甲基-D-天冬氨酸/药物作用受体 N-甲基-D-天冬氨酸/生理学受体神经递质/药物作用受体神经递质/生理学动物男(雄)性大鼠

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Novel strategies for pharmacotherapy of depression

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CURRENT OPINION IN CHEMICAL BIOLOGY 1999年第4期3卷 481-488页

作者： Maubach, KA Rupniak, NMJ Kramer, MS Hill, RG Merck Sharp & Dohme Ltd Neurosci Res Ctr Harlow CM20 2QR Essex England Merck Res Labs W Point PA 19456 USA

Modulating monoamine activity as a therapeutic strategy continues to dominate antidepressant research, with a recent emphasis on agents with multiple targets, including combined serotonin/noradrenaline re-uptake inhibitors and numerous serotonin receptor ligands. An important new development has been the emergence of potential novel mechanisms of action, notably modulation of the activity of neuropeptides substance P and corticotrophin-releasing factor, and the intracellular messenger cyclic adenosine monophosphate. Efforts in this area have recently been rewarded by the demonstration of antidepressant efficacy of the substance P receptor antagonist MK-0869.

关键词：抗抑郁药/治疗应用生物源单胺类/生理学抑郁/药物疗法抑郁/病理生理学单胺氧化酶抑制剂/治疗应用神经肽类/生理学受体神经递质/生理学动物人类

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NEUROBIOLOGY OF CONDITIONING TO DRUGS OF ABUSE

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ANNALS OF THE NEW YORK ACADEMY OF SCIENCES 1992年第1期654卷 335-346页

作者： STEWART, J Center for Studies in Behavioral Neurobiology Department of Psychology Concordia University 1455 de Maisonneuve Boulevard W. Montr&eacute al Qu&eacute bec Canada H3G 1M8

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Role of high-affinity receptors and membrane transporters in nonsynaptic communication and drug action in the central nervous system

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PHARMACOLOGICAL REVIEWS 2000年第1期52卷 63-89页

作者： Vizi, ES Hungarian Acad Sci Inst Expt Med Dept Pharmacol H-1450 Budapest Hungary

Neurochemical and morphological evidence has shown that some neurotransmitters or substances may be released from both synaptic and nonsynaptic sites for diffusion to target cells more distant than those observed in regular synaptic transmission. There are functional interactions between neurons without synaptic contacts, and matches between release sites and localization of receptors sensitive to the chemical signal are exceptions rather than the rule in the central nervous system. This also indicates that besides cabled information signaling (through synapses), there is a "wireless" nonsynaptic interaction between axon terminals. This would be a form of communication transitional between discrete classical neurotransmission (in Sherrington's synapse) and the relatively nonspecific neuroendocrine secretion. Recent findings indicate that in addition to monoamines (norepinephrine, dopamine, serotonin), other transmitters, such as acetylcholine and nitric oxide (NO), may also be involved in these nonsynaptic interactions. It has been shown that NO, an ideal mediator of nonsynaptic communication, can influence the function of uptake carrier systems, which may be an important factor in the regulation of extracellular concentration of different transmitters. This review will focus on the role of nonsynaptic receptors and transporters in presynaptic modulation of chemical transmission in the central nervous system. The nonsynaptic interaction between neurons mediated via receptors and transports of high affinity not localized in synapses has the potential to be an important contributor to the properties and function of neuronal networks. In addition, it will be suggested for the first time that the receptors and transporters expressed nonsynaptically and being of high affinity are the target of drugs taken by the patient.

关键词：细胞间通讯/药物作用细胞间通讯/生理学中枢神经系统/药物作用中枢神经系统/生理学膜/药物作用膜/代谢受体神经递质/药物作用受体神经递质/生理学突触传递/药物作用突触传递/生理学动物人类

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Differential roles of NMDA and non-NMDA receptors in synaptic responses of neurons in nucleus tractus solitarii of the rat

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JOURNAL OF NEUROPHYSIOLOGY 1999年第6期81卷 3034-3043页

作者： Yen, JC Chan, JYH Chan, SHH Natl Sun Yat Sen Univ Ctr Neurosci Kaohsiung 80424 Taiwan Natl Sun Yat Sen Univ Dept Biol Sci Kaohsiung 80424 Taiwan Natl Yang Ming Med Coll Inst Pharmacol Taipei 11221 Taiwan Vet Gen Hosp Kaohsiung Dept Med Educ & Res Kaohsiung 81346 Taiwan

The relative role of N-methyl-D-aspartate (NMDA) and non-NMDA receptors in synaptic responses of neurons in caudal nucleus tractus solitarii (cNTS) was delineated by immunohistochemical and electrophysiologic experiments in rats. Double immunohistochemical staining in in vivo experiments revealed that similar to 80% of cNTS neurons that showed Fos-like immunoreactivity induced by baroreceptor activation were generally also immunoreactive to nonNMDA receptor subunits GluR1 or GluR2. On the other hand, only 20% of Fos-labeled cNTS neurons showed immunoreactivity to NMDA receptor subunits NMDAR1 or NMDAR2. Stimulation of the ipsilateral solitary tract at suprathreshold intensity in slice preparations induced Fos expression in the cNTS and evoked either a single action potential or a complex synaptic response consisting of an initial action potential followed by a secondary slow depolarization. In a majority (70%) of cNTS neurons that exhibited the complex synaptic response, both the initial and secondary components were eliminated reversibly by 6-cyano-7-nitroquinoxaline-2,3-dione (20 mu M). This non-NMDA antagonist also inhibited the single action potential manifested by the other population of cNTS neurons. On the other hand, only the secondary slow depolarization was blocked by D(-)-2-amino-5-phosphonopentanoic acid (250 mu M) or potentiated by NMDA (1.7 mu M). Our results suggested that NMDA and non-NMDA receptors are involved differentially in the synaptic responses of cNTS neurons. Non-NMDA receptors may be distributed predominantly on a majority of the second-order cNTS neurons that may receive primary baroreceptor afferent inputs. On the other hand, NMDA receptors are located primarily on higher-order neurons, which may be connected reciprocally with the second-order cNTS neurons.

关键词： 2-氨基-5-膦酰基戊酸盐/药理学 6-氰-7-硝基喹喔啉-2 3-二酮/药理学电刺激电生理学兴奋性氨基酸拮抗剂/药理学免疫组织化学神经元/药物作用神经元/生理学压力感受器/药物作用压力感受器/生理学原癌基因蛋白质c-fos/生物合成大鼠 Sprague-Dawley 受体 N-甲基-D-天冬氨酸/药物作用受体 N-甲基-D-天冬氨酸/生理学受体神经递质/药物作用受体神经递质/生理学孤束核/细胞学孤束核/药物作用孤束核/生理学动物男(雄)性大鼠

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Extrasynaptic receptors and parasynaptic communication in the brain

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BRAIN RESEARCH BULLETIN 1999年第5-6期50卷 351-352页

作者： Herkenham, M NIMH Funct Neuroanat Sect Bethesda MD 20892 USA

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Distinct synaptic and extrasynaptic NMDA receptors identified in dorsal horn neurones of the adult rat spinal cord

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JOURNAL OF PHYSIOLOGY-LONDON 2000年第3期523卷 621-628页

作者： Momiyama, A Natl Inst Physiol Sci Lab Cerebral Struct Okazaki Aichi 4448585 Japan Nagasaki Univ Sch Med Dept Physiol Nagasaki 8528523 Japan

1. Using patch-clamp recordings, properties of single-channel and synaptic currents mediated by N-methyl-D-aspartate receptors (NMDARs) were examined in substantia gelatinosa (SG) neurones of adult rat spinal cord slices. 2. In somatic outside-out patches, high- and low-conductance NMDAR channels were present. The low-conductance channels exhibited asymmetrical transitions between the main (44 pS) and subconductance (19 pS) levels, suggesting that they arise from NR2D subunit-containing receptors. The high-conductance channels (main conductance, 57 pS) were blocked by ifenprodil, an NR2B subunit selective blocker. 3. Ifenprodil had no effect on NMDA-EPSCs. The double-exponential decay time course and the apparent K-d for Mg2+ of NMDA-EPSCs suggested the expression of NR2A subunit-containing receptors at the synapse. 4. These results indicate that different NMDAR subtypes are expressed in subsynaptic and extrasynaptic regions of adult SG neurones, which may have differential roles in nociception.

关键词：导电性兴奋性突触后电位/药物作用兴奋性突触后电位/生理学离子通道/拮抗剂和抑制剂离子通道/代谢离子通道/生理学镁/药理学神经元/代谢膜片钳术哌啶类/药理学大鼠 Wistar 受体 N-甲基-D-天冬氨酸/分类受体 N-甲基-D-天冬氨酸/药物作用受体 N-甲基-D-天冬氨酸/代谢受体 N-甲基-D-天冬氨酸/生理学受体神经递质/药物作用受体神经递质/代谢受体神经递质/生理学脊髓/细胞学脊髓/代谢胶状质/细胞学胶状质/代谢动物大鼠

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KYNURENIC ACID - A POTENTIAL PATHOGEN IN BRAIN DISORDERS

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ANNALS OF THE NEW YORK ACADEMY OF SCIENCES 1992年第1期648卷 140-153页

作者： SCHWARCZ, R DU, F SCHMIDT, W TURSKI, WA GRAMSBERGEN, JBP OKUNO, E ROBERTS, RC Maryland Psychiatric Research Center University of Maryland School of Medicine Baltimore Maryland 21228

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