Structural Analysis of Alcohol-dependent Activation of GIRKs
GIRK 酒精依赖性激活的结构分析
基本信息
- 批准号:10391737
- 负责人:
- 金额:$ 52.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-07-10 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAffinityAgonistAlcohol consumptionAlcohol dependenceAlcohol withdrawal syndromeAlcoholismAlcoholsAmygdaloid structureAnticonvulsantsBehaviorBehavioralBehavioral ModelBindingBloodBrainCause of DeathChronicComplexEthanolEthanol dependenceExhibitsFDA approvedFiberFundingGIRK1 subunit, G protein-coupled inwardly-rectifying potassium channelGIRK2 subunit, G protein-coupled inwardly-rectifying potassium channelGTP-Binding ProteinsGlutamatesGoalsGrantHippocampus (Brain)HumanInhalationIntoxicationIon ChannelKnockout MiceLeadLegalLigandsMeasuresMedialMediatingMemoryModelingMolecularNeuraxisNeuronsNeurotransmittersNucleus AccumbensPathway interactionsPersonsPharmaceutical PreparationsPharmacologic SubstancePharmacologyPhotometryPotassiumPotassium ChannelPrefrontal CortexPropertyProteinsRewardsTestingUnited StatesWithdrawalWorkalcohol effectalcohol measurementalcohol seeking behavioralcohol use disorderalcohol-related deathanalogbinge drinkingconditioned place preferenceconditioningdopaminergic neuronexcitatory neurongenome wide association studyglutamatergic signalingin vivoinnovationinward rectifier potassium channelmouse modelneurotransmitter releasenovelnovel strategiesnovel therapeuticspreventscreeningsensorsmall moleculestructural biologytoolvapor
项目摘要
Summary
With approximately ninety thousand alcohol-related deaths per year, alcohol is the third leading preventable
cause of death in the United States. Alcohol (ethanol) is addictive and produces complex effects on the body,
primarily through its interactions within the central nervous system. The structural, cellular and circuit
mechanisms by which ethanol imparts its effects on the brain and leads to alcohol use disorders (AUDs) are
poorly understood. A large number of studies have demonstrated that ethanol directly alters the function of ion
channels, such as the G protein-gated inwardly rectifying potassium (GIRK) channel. Studies of GIRK channel
knockout mice and human GWAS also implicate GIRK channels in mediating some of the effects of ethanol in
the brain. However, current pharmacological tools for selectively modulating GIRK channels are limited. The
overall objectives of this grant are to elucidate how ethanol alters brain function and identify new ligands for
treating AUD. Previously, we identified and characterized a GIRK activator, called GiGA1, which selectively
activates GIRK1/GIRK2 channels, does not require G proteins, reduces the excitability of neurons via
activation of endogenously expressed GIRK channels, and exhibits anti-convulsant properties. GiGA1 has not
been thoroughly tested in the context of AUD, however. Here, we hypothesize that GiGA1 activation of
GIRK1/2 channels will mitigate some of the deleterious effects of alcohol on brain reward circuits. Specifically,
we will evaluate the effects of GiGA1 on alcohol-regulated behaviors (conditioned place preference, binge
drinking, and ethanol intake escalation induced by chronic intermittent ethanol vapor inhalation), determine
actions of GiGA1 on alcohol-regulated circuits in the NAc using in vivo fiber photometry to measure activity and
release of neurotransmitters, and develop GIRK2-selective small molecule modulators. Currently, there is a
limited number of FDA approved drugs for treating alcoholism and an urgent need for new approaches for
treating AUD. Defining the physical pocket for ethanol has been critical for understanding how the binding of
ethanol to a channel can lead to changes in channel activity and affect brain function. Now, bridging earlier
studies on how ethanol activates GIRK channels via the alcohol pocket and extending to an innovative
approach of using structural biology to guide screening and selection of novel therapeutics, we are advancing
compounds that directly activate subtypes of GIRK channels and probing their efficacy in mouse models of
AUDs.
总结
每年约有9万人死于酒精相关的疾病,酒精是第三大可预防的疾病。
美国的死因。酒精(乙醇)是上瘾的,对身体产生复杂的影响,
主要是通过其在中枢神经系统内的相互作用。结构、细胞和电路
乙醇对大脑产生影响并导致酒精使用障碍(AUDs)的机制是
不太了解。大量的研究表明,乙醇直接改变了离子的功能,
通道,如G蛋白门控内向整流钾(GIRK)通道。GIRK通道的研究
基因敲除小鼠和人类GWAS也暗示GIRK通道介导了乙醇在体内的某些作用。
大脑然而,目前用于选择性调节GIRK通道的药理学工具有限。的
这项资助的总体目标是阐明乙醇如何改变大脑功能,并确定新的配体,
治疗AUD。以前,我们鉴定并表征了一种GIRK激活剂,称为GiGA 1,它选择性地
激活GIRK 1/GIRK 2通道,不需要G蛋白,通过降低神经元的兴奋性,
激活内源性表达的GIRK通道,并表现出抗惊厥特性。GiGA 1没有
然而,在澳元的背景下进行了彻底的测试。在这里,我们假设GiGA 1激活的
GIRK 1/2通道将减轻酒精对大脑奖励回路的一些有害影响。具体地说,
我们将评估GiGA 1对酒精调节行为(条件性位置偏爱、狂欢)的影响,
饮酒和慢性间歇性乙醇蒸汽吸入引起的乙醇摄入量增加),确定
GiGA 1对NAc中酒精调节回路的作用,使用体内纤维光度法测量活性,
释放神经递质,并开发GIRK 2选择性小分子调节剂。目前,有一个
FDA批准的治疗酒精中毒的药物数量有限,迫切需要新的治疗方法。
治疗AUD。定义乙醇的物理口袋对于理解乙醇的结合是至关重要的。
乙醇进入通道会导致通道活动的变化,影响大脑功能。现在,连接之前
关于乙醇如何通过酒精口袋激活GIRK通道的研究,并扩展到一个创新的
利用结构生物学指导筛选和选择新疗法的方法,我们正在推进
直接激活GIRK通道亚型的化合物,并探测它们在GIRK小鼠模型中的功效。
AUD。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Paul A Slesinger其他文献
Paul A Slesinger的其他文献
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{{ truncateString('Paul A Slesinger', 18)}}的其他基金
Structural analysis of alcohol-dependent activation of GIRKs
GIRK 酒精依赖性激活的结构分析
- 批准号:
9260729 - 财政年份:2010
- 资助金额:
$ 52.85万 - 项目类别:
Structural Analysis of Alcohol-dependent Activation of GIRKs
GIRK 酒精依赖性激活的结构分析
- 批准号:
10640825 - 财政年份:2010
- 资助金额:
$ 52.85万 - 项目类别:
Molecular Changes in Mesolimbic Dopamine Signaling with Psychostimulants
精神兴奋剂中脑边缘多巴胺信号的分子变化
- 批准号:
7661462 - 财政年份:2009
- 资助金额:
$ 52.85万 - 项目类别:
Structural analysis of alcohol-dependent activation of GIRKs
GIRK 酒精依赖性激活的结构分析
- 批准号:
9899904 - 财政年份:2009
- 资助金额:
$ 52.85万 - 项目类别:
Kir 3 Channel Subunits in Drug Abuse with GABAB Agonists
GABAB 激动剂药物滥用中的 Kir 3 通道亚基
- 批准号:
7796607 - 财政年份:2006
- 资助金额:
$ 52.85万 - 项目类别:
Kir 3 Channel Subunits in Drug Abuse with GABAB Agonists
GABAB 激动剂药物滥用中的 Kir 3 通道亚基
- 批准号:
7097633 - 财政年份:2006
- 资助金额:
$ 52.85万 - 项目类别:
Kir 3 Channel Subunits in Drug Abuse with GABAB Agonists
GABAB 激动剂药物滥用中的 Kir 3 通道亚基
- 批准号:
7587306 - 财政年份:2006
- 资助金额:
$ 52.85万 - 项目类别:
Kir 3 Channel Subunits in Drug Abuse with GABAB Agonists
GABAB 激动剂药物滥用中的 Kir 3 通道亚基
- 批准号:
7388790 - 财政年份:2006
- 资助金额:
$ 52.85万 - 项目类别:
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