Molecular Studies of Brain NMDA Receptors

脑 NMDA 受体的分子研究

• 批准号: 7588064
• 负责人: R. Suzanne Zukin
• 金额: $ 36.4万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 2011-03-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7588064
• 关键词: AIDS Dementia Complex; Acute; Adaptor Signaling Protein; Age; Alzheimer' s Disease; Amino Acids; Birth; Brain; Brain Diseases; Calcium; Calcium Signaling; Cells; Cessation of life; Complex; Coupling; Craniocerebral Trauma; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; D Aspartate; Data; Dendritic Spines; Development; Disease; Epilepsy; Genes; Grant; Hippocampus (Brain); Huntington Disease; Image; Laboratories; Learning; Long-Term Potentiation; Mediating; Memory; Molecular; Molecular Target; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR1 gene; NR2B NMDA receptor; Neonatal; Neurons; Permeability; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Population; Process; Protein Dephosphorylation; Protein phosphatase; Proteins; Protocols documentation; Receptor Signaling; Recombinants; Regulation; Research; Research Personnel; Schizophrenia; Signal Transduction; Signaling Molecule; Site; Slice; Stroke; Synapses; Synaptic Receptors; Synaptic Transmission; Synaptic plasticity; Testing; Vertebral column; aspartate receptor; base; cognitive function; density; extracellular; genetic analysis; link protein; neuronal circuitry; novel; overexpression; patch clamp; postnatal; postsynaptic; programs; receptor; scaffold; synaptic function; synaptogenesis; transmission process

DESCRIPTION (provided by applicant): Ca2+ influx through NMDARs (N-methyl-D-aspartate receptors) triggers long-lasting changes; in synaptic efficacy such as LTP (long-term potentiation). The NMDAR-mediated rise in postsynaptic Ca2+ activates a network of kinases and phosphatases that promotes long-lasting changes in synaptic strength. Recent findings by our laboratories indicate that Ca2+ permeability of neuronal NMDARs and NMDAR-mediated Ca2+ influx during induction of LTP are under the control of the cAMP/PKA signaling cascade. Moreover, PKA modulates NMDAR-mediated Ca2+ rises in activated dendritic spines. Our data link PKA-dependent synaptic plasticity to Ca2+ signalling in spines and thus provide a novel mechanism whereby PKA regulates induction of LTP. SPECIFIC AIMS are as follows: 1) To examine mechanisms underlying PKA modulation of Ca2+ permeability of synaptic (NR1/NR2A) vs. extrasynaptic (NR1/NR2B) NMDARs in hippocampal neurons. Although our data show that PKA selectively modulates Ca2+ permeability of synaptic NMDARs, the impact of PKA activation on extra-synaptic NMDARs is less clear. We hypothesize that PKA differentially modulates synaptic and extra-synaptic NMDARs. We further propose that extracellular signals that modulate cAMP or protein phosphatases at postsynaptic sites will bi-directionally regulate Ca2+ permeation through synaptic NMDARs and induction of LTP. 2) To examine developmental regulation of PKA actions on NMDAR-mediated Ca+ influx in dendritic spines. Although PKA modulates Ca2+ permeability of NMDARs in mature brain, the impact of PKA activation on synaptic (NR1/NR2B) NMDARs in neonatal brain is less clear. At birth, NMDARs contain NR1 and NR2B subunits. During postnatal development, there is a progressive inclusion of the NR2A subunit. Preliminary studies with recombinant NMDARs suggest that PKA differentially regulates NR2A- vs. NR2B-containing receptors. Thus, we hypothesize that PKA modulation of NMDAR-mediated currents is less selective at early ages and becomes highly selective for NMDAR-mediated Ca2+ influx at mature synapses. 3) To identify the molecular target of PKA that controls Ca2+ permeation through NMDARs. Although the NMDAR is a known functional target of PKA, the molecular target that control Ca2+ permeation through NMDARs is unknown. We hypothesize that PKA phosphorylates one or more residues on NR1 or NR2A/B subunit and thereby alters the geometry of the channel pore; when PKA is inactive, NMDARs are rapidly dephosphorylated. The cAMP/PKA signalling cascade and calcium are crucial for synaptic plasticity. Given the widespread localization of NMDARs and PKA in the CNS, regulation of NMDA function by PKA is a powerful mechanism to modulate synaptic efficacy. Ca2+ influx via NMDARs is also implicated in the excitotoxic neuronal death associated with stroke, epilepsy, head trauma, Huntington's disease, Alzheimer's disease, AIDS/dementia, and schizophrenia. Findings from the proposed studies are relevant to our understanding of these devastating and often fatal disorders.

描述（由申请人提供）：通过NMDARS（N-甲基-D-天冬氨酸受体）CA2+涌入触发了长期变化；在LTP（长期增强）等突触功效中。 NMDAR介导的突触后CA2+的上升激活了激酶和磷酸酶网络，从而促进了突触强度的持久变化。我们的实验室的最新发现表明，在LTP诱导过程中，神经元NMDAR和NMDAR介导的Ca2+涌入的Ca2+渗透性受CAMP/PKA信号级联的控制。此外，PKA调节活化的树突状刺中NMDAR介导的Ca2+上升。我们的数据将依赖PKA的突触可塑性与棘中的Ca2+信号传导联系起来，从而提供了一种新型机制，从而使PKA调节LTP的诱导。具体目的如下：1）检查在海马神经元中突触（NR1/NR2A）与突触外（NR1/NR2B）NMDARS的CA2+渗透性的基础机制。尽管我们的数据表明，PKA选择性调节突触NMDAR的Ca2+渗透性，但PKA激活对外突触外NMDAR的影响尚不清楚。我们假设PKA差异调节突触和突触外NMDAR。我们进一步提出，在突触后部位调节cAMP或蛋白质磷酸酶的细胞外信号将通过突触NMDAR和LTP诱导来调节Ca2+渗透。 2）检查对树突状棘中NMDAR介导的CA+流入的PKA作用的发育调控。尽管PKA调节了成熟大脑中NMDAR的Ca2+渗透性，但PKA激活对新生儿大脑中突触（NR1/NR2B）NMDAR的影响尚不清楚。出生时，NMDAR包含NR1和NR2B亚基。 在产后发育期间，NR2A亚基逐渐纳入了。重组NMDAR的初步研究表明，PKA差异调节NR2A-与NR2B的受体。因此，我们假设NMDAR介导的电流的PKA调制在早期的选择性较小，并且对成熟突触时的NMDAR介导的Ca2+流入变得高度选择性。 3）确定通过NMDAR控制Ca2+渗透的PKA的分子靶标。尽管NMDAR是PKA的已知功能靶标，但通过NMDAR控制Ca2+渗透的分子靶标尚不清楚。我们假设PKA磷酸化NR1或NR2A/B亚基上的一个或多个残基，从而改变了通道孔的几何形状。当PKA不活跃时，NMDAR会迅速脱磷酸化。营地/PKA信号级联和钙对于突触可塑性至关重要。鉴于NMDAR和PKA在中枢神经系统中的广泛定位，PKA对NMDA功能的调节是调节突触功效的强大机制。 Ca2+通过NMDAR的涌入还与中风，癫痫，头部创伤，亨廷顿氏病，阿尔茨海默氏病，艾滋病/痴呆症和精神分裂症有关的兴奋性神经元死亡。提出的研究的发现与我们对这些毁灭性和致命性疾病的理解有关。

项目成果

Synapse-specific metaplasticity: to be silenced is not to silence 2B.

突触特异性的化塑性：沉默并不是沉默 2B。

• DOI: 10.1016/j.neuron.2010.06.014
• 发表时间: 2010
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Philpot,BenjaminD;Zukin,RSuzanne
• 通讯作者: Zukin,RSuzanne

Regulation of NMDA receptor Ca2+ signalling and synaptic plasticity.

• DOI: 10.1042/bst0371369
• 发表时间: 2009-12
• 期刊: Biochemical Society transactions
• 影响因子: 3.9
• 作者: Lau CG;Takeuchi K;Rodenas-Ruano A;Takayasu Y;Murphy J;Bennett MV;Zukin RS
• 通讯作者: Zukin RS

N-methyl-D-aspartate activates different channels than do kainate and quisqualate.

N-甲基-D-天冬氨酸激活的通道与红藻氨酸和使君子氨酸不同。

• DOI: 10.1073/pnas.86.6.2083
• 发表时间: 1989
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Lerma,J;Kushner,L;Zukin,RS;Bennett,MV
• 通讯作者: Bennett,MV

Glutamate receptor gene expression in spinal cord of arthritic rats.

关节炎大鼠脊髓中谷氨酸受体基因的表达。

• DOI: 10.1523/jneurosci.14-03-01576.1994
• 发表时间: 1994
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Pellegrini-Giampietro,DE;Fan,S;Ault,B;Miller,BE;Zukin,RS
• 通讯作者: Zukin,RS

mRNA from NCB-20 cells encodes the N-methyl-D-aspartate/phencyclidine receptor: a Xenopus oocyte expression study.

NCB-20 细胞的 mRNA 编码 N-甲基-D-天冬氨酸/苯环己哌啶受体：非洲爪蟾卵母细胞表达研究。

• DOI: 10.1073/pnas.86.5.1708
• 发表时间: 1989
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Lerma,J;Kushner,L;Spray,DC;Bennett,MV;Zukin,RS
• 通讯作者: Zukin,RS