Mechanisms of Neuronal Calcineurin-NFAT Synapse-to-Nucleus Signaling

神经元钙调神经磷酸酶-NFAT 突触至细胞核信号转导机制

• 批准号: 9815268
• 负责人: MARK L DELL'ACQUA
• 金额: $ 3.89万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9815268
• 关键词: A kinase anchoring protein; Acute; Aging; Alzheimer' s Disease; Attention deficit hyperactivity disorder; Binding; Biochemical; Bipolar Disorder; Brain; Calcineurin; Calcium Channel; Calcium Signaling; Calcium ion; Calmodulin; Candidate Disease Gene; Cell Communication; Cell Mobility; Cell Nucleus; Code; Communication; Complex; Coupling; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic AMP-Responsive DNA-Binding Protein; Data; Dendrites; Dendritic Spines; Development; Distal; Docking; Down Syndrome; Electric Stimulation; Expression Profiling; Feedback; Fluorescence Recovery After Photobleaching; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Glutamate Receptor; Glutamates; Goals; Hippocampus (Brain); Image; Impaired cognition; Inherited; Intellectual functioning disability; Knock-in Mouse; Lasers; Lead; Learning; Leucine Zippers; Link; Major Depressive Disorder; Measures; Membrane; Memory; Molecular; Monitor; Mus; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Nuclear Translocation; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphotransferases; Positioning Attribute; Process; Protein Kinase; Proteins; Receptor Activation; Regulation; Reporter Genes; Research Design; Risk; Scaffolding Protein; Schizophrenia; Shapes; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Slice; Synapses; Synaptic plasticity; T-Cell Activation; Testing; Time; Timothy syndrome; Transcriptional Activation; Transcriptional Regulation; Vertebral column; activating transcription factor; autism spectrum disorder; base; beta-adrenergic receptor; cellular imaging; genome wide association study; imaging approach; live cell imaging; mRNA Expression; mutant; nervous system disorder; neuronal cell body; neuropsychiatric disorder; novel; novel therapeutics; nuclear factors of activated T-cells; postsynaptic; postsynaptic neurons; programs; recruit; response; spatiotemporal; transcription factor; transcriptome sequencing; voltage

Mechanisms of Neuronal Calcineurin-NFAT Synapse-to-Nucleus Signaling Project Summary/Abstract In hippocampal neurons, somato-dendritic CaV1.2 L-type voltage-gated Ca2+ channels (LTCC) function in excitation-transcription (E-T) coupling. Depolarizations that open LTCCs in postsynaptic neurons activate the transcription factors cAMP-response element binding protein (CREB) and nuclear factor of activated T-cells (NFAT) through Ca2+-regulated kinases and phosphatases. Because LTCC transcriptional regulation is required for long-lasting forms of excitatory synaptic plasticity that underlie learning and memory, it is crucial to understand how LTCC signaling leads to efficient, spatiotemporally specific synapse-to-nucleus communication. A question of fundamental importance in synapse-to-nucleus signaling is: how are early signals in E-T coupling―Ca2+ signals in dendritic postsynaptic nanodomains―transduced into signals that are reliably relayed over long distances to the nucleus? The postsynaptic scaffold protein A-kinase anchoring protein (AKAP) 79/150 binds to CaV1.2 through a modified leucine zipper (LZ) motif. This AKAP anchors both the cAMP- dependent protein kinase (PKA), via an amphipathic α-helical motif, and the Ca2+-calmodulin (CaM)-activated protein phosphatase-2B (calcineurin; CaN), via an atypical PxIxIT docking motif. Anchoring of PKA to AKAP79/150 supports enhancement of neuronal LTCC current amplitude that is potently opposed by Ca2+-dependent feedback through AKAP-anchored CaN. LTCC activation of AKAP-localized CaN is also required for K+ depolarization-triggered NFAT translocation to the nucleus and activation of transcription. However, key synapse-to-nucleus signaling questions remain for the LTCC-AKAP-CaN-NFAT pathway: (1) does the AKAP79/150 signaling complex regulate LTCC Ca2+ influx specifically in dendrites excited by postsynaptic glutamate receptor activation; (2) do these Ca2+ signals in dendrites locally activate CaN-NFAT signaling that ultimately acts in the nucleus; (3) what are the neuronal target genes regulated by this signaling pathway; and (4) is this process engaged during synaptic plasticity? We will explore these crucial questions in three aims that rely upon a combination of Ca2+ imaging (Aim 1), CaN and NFAT imaging (Aim 2), and gene transcription analyses (Aim 3). AKAP79/150 regulation of LTCC Ca2+ influx, CaN-NFAT signaling dynamics, and activity-dependent gene transcription will be investigated in neurons or brain slices expressing AKAP mutants that alter PKA anchoring, CaN anchoring, or LZ domain binding. The overall goal of this project is to test a central hypothesis in synapse-to-nucleus communication that postsynaptic Ca2+ signals are locally re-coded in dendrites as protein-based signals (e.g., NFAT), and relayed to the nucleus to control plasticity-associated gene expression.

神经元钙调磷酸酶- nfat突触-核信号传导机制