State-dependent interaction of antiepileptic drugs with voltage-dependent sodium channels and differential regulation of excitatory and inhibitory central neurons
State-dependent interaction of antiepileptic drugs with voltage-dependent sodium channels and differential regulation of excitatory and inhibitory central neurons
批准号:
10332723
负责人:
BRUCE P BEAN
金额:
$47.47万
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
项目状态:
已结题
起止时间:
2019-02-01 至 2024-01-31
关键词:
Action PotentialsAcuteAddressAffinityAntiepileptic AgentsAxonBindingBrainBullaCannabidiolCarbamazepineClinicalClosure by clampDataDependenceDrug InteractionsDrug TargetingExperimental DesignsFire - disastersFrequenciesGlutamatesGoalsInterneuronsKineticsLaboratoriesLeadLidocaineMembraneNeuronsPathologicPatternPharmaceutical PreparationsPhenytoinPhysiologicalPreparationPropertyRegulationResearchRestSeizuresSliceSodiumSodium ChannelTechniquesTestingWorkbiophysical techniquesdrug actionexcitatory neuronexperimental studyfollow-uphippocampal pyramidal neuroninhibitory neuronlamotriginenovelvoltagevoltage clamp
中文摘要
拟议研究的目标是采取生物物理学的方法来了解抗癫痫是如何发生的
英文摘要
The goal of the proposed research is to take a biophysical approach to understand how antiepileptic
drugs targeted to voltage-dependent sodium channels regulate neuronal firing by differentially binding to
different gating states of the channels. The work brings together two lines of research in the laboratory,
one characterizing the state-dependent interaction of drugs like lidocaine, phenytoin, carbamazepine,
and lacosamide with sodium channels and the other exploring how gating of sodium channels regulates
firing of a variety of mammalian central neurons. A key property of antiepileptic drugs is differential
binding to different gating states of sodium channels, but how this changes firing of particular kinds of
central neurons to control pathological neuronal activity is poorly understood. For example, higher affinity
binding to open and inactivated states results in use-dependence, with increased inhibition as channels
cycle through open and inactivated states during action potentials. Yet, this does not easily explain their
clinical action, because use-dependence might predict more potent inhibition of GABAergic inhibitory
neurons, which typically fire at high frequencies, than glutamatergic excitatory neurons, which typically
fire more slowly. We will examine how antiepileptic drugs interact with the gating of neuronal sodium channels and
explore how state-dependent binding and unbinding regulates the firing patterns of a variety of excitatory
and inhibitory neurons. We will follow up preliminary data showing that carbamazepine, phenytoin, and
lamotrigine are all more effective in inhibiting firing of slower-firing glutamatergic pyramidal neurons than
fast-spiking GABAergic neurons. We will analyze how these drugs and others (including the new anti-
epileptic cannabidiol and a novel, more potent carbamazepine derivative) interact with gating of both
native and cloned sodium channels and how the resulting changes in sodium current modify the firing
patterns of a variety of excitatory and inhibitory neurons in a manner depending on the repertoire of other
channels. The experimental design will combine recordings of action potential firing with voltage-clamp
analysis of the underlying sodium currents, using intact neurons in brain slice, acutely dissociated
neurons, and heterologously expressed cloned channels. A key feature will be to study action potential
firing, channel gating kinetics, and drug action at 37 °C.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Ion Channel Pharmacology for Pain and Epilepsy
-
批准号:10449483
-
项目类别:
-
资助金额:$33.4万
-
财政年份:2022
-
负责人:BRUCE P BEAN
-
依托单位:
Ion Channel Pharmacology for Pain and Epilepsy
-
批准号:10615776
-
项目类别:
-
资助金额:$108.71万
-
财政年份:2022
-
负责人:BRUCE P BEAN
-
依托单位:
Voltage-dependent ion channels controlling firing patterns of central neurons
-
批准号:10225152
-
项目类别:
-
资助金额:$16.81万
-
财政年份:2020
-
负责人:BRUCE P BEAN
-
依托单位:
TRP Channel Mediated Pain Circuitry
-
批准号:8299023
-
项目类别:
-
资助金额:$138.22万
-
财政年份:2011
-
负责人:BRUCE P BEAN
-
依托单位:
TRP Channel Mediated Pain Circuitry
-
批准号:8153242
-
项目类别:
-
资助金额:$143.78万
-
财政年份:2011
-
负责人:BRUCE P BEAN
-
依托单位:
TRP Channel Mediated Pain Circuitry
-
批准号:8541064
-
项目类别:
-
资助金额:$130.73万
-
财政年份:2011
-
负责人:BRUCE P BEAN
-
依托单位:
Selective targeting of sodium channel blockers to pain-sensing neurons
-
批准号:8290395
-
项目类别:
-
资助金额:$36.34万
-
财政年份:2009
-
负责人:BRUCE P BEAN
-
依托单位:
Selective targeting of sodium channel blockers to pain-sensing neurons
-
批准号:8068184
-
项目类别:
-
资助金额:$36.34万
-
财政年份:2009
-
负责人:BRUCE P BEAN
-
依托单位:
Selective targeting of sodium channel blockers to pain-sensing neurons
-
批准号:7729878
-
项目类别:
-
资助金额:$37.06万
-
财政年份:2009
-
负责人:BRUCE P BEAN
-
依托单位:
Selective targeting of sodium channel blockers to pain-sensing neurons
-
批准号:8119847
-
项目类别:
-
资助金额:$8.48万
-
财政年份:2009
-
负责人:BRUCE P BEAN
-
依托单位:
Ion channels in suprachiasmatic nucleus neurons
-
批准号:6767435
-
项目类别:
-
资助金额:$32.56万
-
财政年份:2004
-
负责人:BRUCE P BEAN
-
依托单位:
Ion channels in suprachiasmatic nucleus neurons
-
批准号:7215279
-
项目类别:
-
资助金额:$30.94万
-
财政年份:2004
-
负责人:BRUCE P BEAN
-
依托单位:
Ion channels in suprachiasmatic nucleus neurons
-
批准号:7047711
-
项目类别:
-
资助金额:$31.86万
-
财政年份:2004
-
负责人:BRUCE P BEAN
-
依托单位:
Ion channels in suprachiasmatic nucleus neurons
-
批准号:6874905
-
项目类别:
-
资助金额:$32.63万
-
财政年份:2004
-
负责人:BRUCE P BEAN
-
依托单位:
ACETYLCHOLINE MODULATION OF ION CHANNELS AND FIRING PATTERNS
-
批准号:6565270
-
项目类别:
-
资助金额:$29.59万
-
财政年份:2001
-
负责人:BRUCE P BEAN
-
依托单位:
ACETYLCHOLINE MODULATION OF ION CHANNELS AND FIRING PATTERNS
-
批准号:6410666
-
项目类别:
-
资助金额:$29.59万
-
财政年份:2000
-
负责人:BRUCE P BEAN
-
依托单位:
ACETYLCHOLINE MODULATION OF ION CHANNELS AND FIRING PATTERNS
-
批准号:6302882
-
项目类别:
-
资助金额:$19.78万
-
财政年份:1999
-
负责人:BRUCE P BEAN
-
依托单位:
ACETYLCHOLINE MODULATION OF ION CHANNELS AND FIRING PATTERNS
-
批准号:6112664
-
项目类别:
-
资助金额:$19.78万
-
财政年份:1998
-
负责人:BRUCE P BEAN
-
依托单位:
ACETYLCHOLINE MODULATION OF NEURONAL EXCITABILITY
-
批准号:6126360
-
项目类别:
-
资助金额:$93.74万
-
财政年份:1998
-
负责人:BRUCE P BEAN
-
依托单位:
ACETYLCHOLINE MODULATION OF NEURONAL EXCITABILITY
-
批准号:6625533
-
项目类别:
-
资助金额:$101.95万
-
财政年份:1998
-
负责人:BRUCE P BEAN
-
依托单位:
海外基金