Sodium and Calcium Channels: Structure, Function, Neuroplasticity, and Disease

钠和钙通道:结构、功能、神经可塑性和疾病

基本信息

  • 批准号:
    10391434
  • 负责人:
  • 金额:
    $ 111.16万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-05-01 至 2027-04-30
  • 项目状态:
    未结题

项目摘要

Voltage-gated sodium (Nav) and calcium (Cav) channels generate action potentials and initiate synaptic transmission in neurons. Mutations in them cause inherited epilepsy, migraine, chronic pain, and periodic paralysis, and they are important molecular targets for drugs. A. New insights into structure and function of Nav channels have come from our high-resolution x-ray crystallography of their bacterial ancestor NavAb. We will further define the structural basis for key functional properties of mammalian Nav channels by building their characteristic structural features into NavAb, including the structural basis for voltage-dependent activation, ion selectivity, and fast inactivation. Based on these results, we will determine the structural basis for impaired Nav channel function by mutations that cause periodic paralysis and the chronic pain syndromes erythromelalgia and paroxysmal extreme pain disorder. B. Failure of learning and memory is a debilitating aspect of aging and neurodegenerative disease, yet we do not understand the basic mechanisms of these crucial brain processes and we cannot intervene effectively in these deficits. Learning and memory takes place primarily at synapses. Presynaptic calcium (Cav2.1) channels initiate neurotransmitter release at most synapses in the brain. The activity of these channels is tightly regulated by a large complex of signaling proteins, including calmodulin and related calcium-sensor proteins. Our work implicates Cav2.1 channel regulation in short-term synaptic plasticity in transfected synapses in cultured neurons and in a novel mouse model in which the IM-AA mutation is inserted into Cav2.1. We will further define the molecular and structural mechanism for Cav2.1 channel regulation, determine the role of regulation of Cav2.1 channels in short-term synaptic plasticity of neural circuits, and explore the role of regulation of Cav2.1 channels and short-term synaptic plasticity in spatial learning and memory. Our experiments with this unique mouse model will give unique insights into the mechanism of short-term presynaptic plasticity in hippocampal neurons and its role in integrative bbrain function. C. Dravet Syndrome (DS) is a devastating childhood neuropsychiatric disorder caused by de novo, heterozygous loss-of-function mutations in Nav1.1. We developed a mouse genetic model with all the features of DS, including thermally induced and spontaneous seizures, ataxia, circadian rhythm and sleep disorders, cognitive deficit, autistic-like features, and premature death via SUDEP. Physiological and genetic studies show that all these effects are correlated with loss of Na currents and excitability of GABAergic interneurons, without consistent effects on excitatory neurons, which causes imbalance of excitation vs. inhibition in neural circuits. To further advance understanding of pathophysiology and treatment of DS, we will determine the neural cells and circuits responsible for DS using specific deletion by the Cre-Lox method, identify the sites of hyperexcitability in neural cells and circuits that appear first in DS mice in vivo, and optimize next-generation combination therapy for seizures, status epilepticus, cognitive deficit, and premature death in DS.
电压门控钠(Nav)和钙(Cav)通道产生动作电位并启动突触

项目成果

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WILLIAM A CATTERALL其他文献

WILLIAM A CATTERALL的其他文献

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{{ truncateString('WILLIAM A CATTERALL', 18)}}的其他基金

Sodium and Calcium Channels: Structure, Function, Neuroplasticity, and Disease
钠和钙通道:结构、功能、神经可塑性和疾病
  • 批准号:
    10614398
  • 财政年份:
    2019
  • 资助金额:
    $ 111.16万
  • 项目类别:
Sodium and Calcium Channels: Structure, Function, Neuroplasticity, and Disease
钠和钙通道:结构、功能、神经可塑性和疾病
  • 批准号:
    9923774
  • 财政年份:
    2019
  • 资助金额:
    $ 111.16万
  • 项目类别:
Structural Basis for Calcium Selectivity and Drug Block of Cav Channels
Cav 通道钙选择性和药物阻断的结构基础
  • 批准号:
    9195112
  • 财政年份:
    2014
  • 资助金额:
    $ 111.16万
  • 项目类别:
Leica SP8 WWL Confocal Microscope
Leica SP8 WWL 共焦显微镜
  • 批准号:
    8639342
  • 财政年份:
    2014
  • 资助金额:
    $ 111.16万
  • 项目类别:
Structural Basis for Antiarrhythmic Drug Action
抗心律失常药物作用的结构基础
  • 批准号:
    10063882
  • 财政年份:
    2012
  • 资助金额:
    $ 111.16万
  • 项目类别:
Structural Basis for Antiarrhythmic Drug Action
抗心律失常药物作用的结构基础
  • 批准号:
    8604411
  • 财政年份:
    2012
  • 资助金额:
    $ 111.16万
  • 项目类别:
Structural Basis for Antiarrhythmic Drug Action
抗心律失常药物作用的结构基础
  • 批准号:
    8454453
  • 财政年份:
    2012
  • 资助金额:
    $ 111.16万
  • 项目类别:
Structural Basis for Antiarrhythmic Drug Action
抗心律失常药物作用的结构基础
  • 批准号:
    10364048
  • 财政年份:
    2012
  • 资助金额:
    $ 111.16万
  • 项目类别:
Structural Basis for Antiarrhythmic Drug Action
抗心律失常药物作用的结构基础
  • 批准号:
    8270797
  • 财政年份:
    2012
  • 资助金额:
    $ 111.16万
  • 项目类别:
Automated Patch Clamp Shared Instrumentation
自动化膜片钳共享仪器
  • 批准号:
    7791042
  • 财政年份:
    2010
  • 资助金额:
    $ 111.16万
  • 项目类别:

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