Alpha-Conotoxin MII: A Selective Nicotinic Receptor Probe
Alpha-Conotoxin MII: A Selective Nicotinic Receptor Probe
批准号:
8116617
负责人:
PAUL WHITEAKER
金额:
$35.53万
依托单位国家:
美国
项目类别:
财政年份:
1999
资助国家:
美国
项目状态:
已结题
起止时间:
1999-02-01 至 2014-08-31
关键词:
AddressAdoptedAffectAminobutyric AcidsAnimalsBehavioralBindingBiological AssayBiotinChronicComplex MixturesConotoxinConus genusCorpus striatum structureDevelopmentDopamineDrosophila acetylcholine receptor alpha-subunitEngineeringEquilibriumExhibitsFamilyFundingGoalsGrantHealthHumanHybridsIndividualKnowledgeLabelLesionLigand BindingLigandsLocationMaintenanceMeasuresMediatingModelingMolecularMusMutationNeurotransmittersNicotineNicotine DependenceNicotinic ReceptorsParkinson DiseasePeptidesPerformancePlayPopulationProgress ReportsPropertyRadiolabeledResearch PersonnelRetinal ConeRoleSeriesSnailsSpecificitySystemToxinVariantalpha-Conotoxinalpha-conotoxin MIIanalogbasedesignexperiencegain of functiongamma-Aminobutyric Acidimprovedinsightmemberneurotransmissionnovelprogramsradiotracerreceptorresearch studyresponsesmoking cessationsuccesstool
中文摘要
描述(由申请方提供):尼古丁通过多种烟碱乙酰胆碱受体(nAChR)家族产生行为效应。尼古丁诱发的多巴胺释放被认为在尼古丁依赖的建立和维持中起重要作用,这使得人们继续使用烟草产品,尽管它们对健康的危害是众所周知的。α-芋螺毒素MII是一种从捕食性锥形蜗牛Conusmagus中分离的毒素,其区分烟碱受体的亚类。在该资助的第一个资助期内,我们使用α-CtxMII来识别和分析调节尼古丁引起的多巴胺释放的nAChR群体。我们还开始研究长期尼古丁暴露对这些受体的影响,以及它们在帕金森病模型中的作用。为了增强α-CtxMII的有用性,我们还设计了具有新特性或增加其对特定nAChR群体的选择性的变体。本提案中概述的实验将进一步扩展这些研究。1)慢性治疗和烟碱亚基突变将(单独或组合)用于研究在前一个资助期内表征的nAChR群体如何相互作用,以及它们调节的神经递质系统。2)将开发新的α-CtxMII衍生物,目的有二。首先,制备α 3 β 2-nAChR亚型选择性衍生物(我们目前没有这样的化合物,但这是一种天然表达的nAChR亚型,需要进一步研究)。第二,生产基于α-CtxMII的放射性标记,保留[125 I] α-CtxMII的原始选择性(在先前的资助期内开发),但具有改进的测定性能。这将提高我们测量和研究这些重要的nAChR的能力。3)合成并表征对α 7亚型nAChR具有选择性的α-芋螺毒素ArIB的衍生物。我们打算开发一系列有用的,高选择性的工具,这种自然发生的nAChR亚型的研究。拟议的研究将进一步深入了解天然存在的nAChR的位置,数量和功能作用,以及它们之间的相互作用。这很可能是增加的理解将,反过来,阐明哪些nAChR亚型涉及尼古丁依赖,从而有助于尝试开发更有效的戒烟援助。这些见解也可以指导其他疾病的尼古丁疗法的设计。
英文摘要
DESCRIPTION (provided by applicant): Nicotine produces behavioral effects through a diverse family of nicotinic acetylcholine receptors (nAChRs). Nicotine-evoked dopamine release is thought to play an important role in the establishment and maintenance of nicotine dependence, which undelies peoples' continued use of tobacoo products, despite their well-known dangers to health. alpha-conotoxin MII is a toxin isolated from the predatory cone-snail Conus magus, which distinguishes between subsets of nicotinic receptors. In the first funding periods of this grant, we used alpha-CtxMII to identify and analyse the nAChR populations that modulate nicotine-evoke dopamine release. We also began to study the effects of chronic nicotine exposure on these receptors, and how they are affected in models of Parkinson's Disease. In order to enhance the usefulness of alpha-CtxMII, we have also engineered variants which have incorporate new properties or increased its selectivity for particular nAChR populations. Experiments outlined in the current proposal will extend these studies further. 1) Chronic treatment and nicotinic subunit mutation will be used (alone, and in combination) to investigate how the nAChR populations characterized in the previous funding period interact with each other, and with the neurotransmitter systems that they modulate. 2) New alpha-CtxMII derivatives will be developed with two aims. First, to make alpha3beta2-nAChR subtype selective derivatives (we do not have such a compound at present, but this is a natually-expressed nAChR subtype that requires further study). Second, to produce alpha-CtxMII-based radiolabels that retain the original selectivity of [125l]alpha-CtxMII (which was developed in the previous funding periods), but with improved assay performance. This will improve out ability to measure and study these important nAChRs. 3) Synthesize and characterize derivatives of alpha-conotoxin ArIB, which has selectivity for alpha7-subtype nAChRs. We intend to develop a series of useful, highly-selective tools for the study of this naturally-occurring nAChR subtype. The proposed studies will provide further insights into the locations, numbers and functional roles of naturally-occurring nAChRs, and the interactions between them. It is likely that this increased understanding will, in turn, illuminate which nAChR subtypes are implicated in nicotine dependence, and thus assist in attempts to develop more-effective smoking cessation aids. These insights may also guide the design of nicotinic therapies for other conditions.
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DOI:
10.1016/j.bcp.2013.05.021
发表时间:
2013-10-15
期刊:
Biochemical pharmacology
影响因子:
5.8
作者:
[Marks MJ]
通讯作者:
Marks MJ
DOI:
10.1007/978-3-540-69248-5_4
发表时间:
2009-01-01
期刊:
Handbook of experimental pharmacology
影响因子:
--
作者:
[Collins, Allan C, Salminen, Outi, Grady, Sharon R]
通讯作者:
Grady, Sharon R
A role for *4(non-*6)* nicotinic acetylcholine receptors in motor behavior.
*4(非-*6)*烟碱乙酰胆碱受体在运动行为中的作用。
DOI:
10.1016/j.neuropharm.2013.05.001
发表时间:
2013
期刊:
Neuropharmacology
影响因子:
4.7
作者:
[Soll,LindseyG, Grady,SharonR, Salminen,Outi, Marks,MichaelJ, Tapper,AndrewR]
通讯作者:
Tapper,AndrewR
DOI:
10.1523/jneurosci.0937-11.2011
发表时间:
2011-07-27
期刊:
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子:
--
作者:
[McGranahan TM, Patzlaff NE, Grady SR, Heinemann SF, Booker TK]
通讯作者:
Booker TK
Loss of alpha-conotoxinMII- and A85380-sensitive nicotinic receptors in Parkinson's disease striatum.
帕金森病纹状体中 α-芋螺毒素 MII 和 A85380 敏感烟碱受体的丧失。
DOI:
10.1111/j.1471-4159.2004.02177.x
发表时间:
2004
期刊:
Journal of neurochemistry
影响因子:
4.7
作者:
[Quik,M, Bordia,T, Forno,L, McIntosh,JM]
通讯作者:
McIntosh,JM
共 8 条
Relevance of α-Conotoxin MII Sensitive Nicotinic Receptor Subtypes to Nicotine Addiction
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批准号:10600540
-
项目类别:
-
资助金额:$55.0万
-
财政年份:2022
-
负责人:PAUL WHITEAKER
-
依托单位:
Relevance of α-Conotoxin MII Sensitive Nicotinic Receptor Subtypes to Nicotine Addiction
-
批准号:9212601
-
项目类别:
-
资助金额:$56.72万
-
财政年份:2017
-
负责人:PAUL WHITEAKER
-
依托单位:
High-Throughput Assay Development for Non-Nicotine Tobacco Components
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批准号:8576344
-
项目类别:
-
资助金额:$23.01万
-
财政年份:2013
-
负责人:PAUL WHITEAKER
-
依托单位:
High-Throughput Assay Development for Non-Nicotine Tobacco Components
-
批准号:8660057
-
项目类别:
-
资助金额:$23.25万
-
财政年份:2013
-
负责人:PAUL WHITEAKER
-
依托单位:
HTS Assay Development for alpha6/3beta2beta3 Subtype Nicotinic Receptors
-
批准号:8212661
-
项目类别:
-
资助金额:$25.4万
-
财政年份:2011
-
负责人:PAUL WHITEAKER
-
依托单位:
Construction and Expression of Concatemeric alpha6beta2* Nicotinic Acetycholine R
-
批准号:7641663
-
项目类别:
-
资助金额:$19.13万
-
财政年份:2009
-
负责人:PAUL WHITEAKER
-
依托单位:
Immunochemical Protocols for Nicotinic Receptors
-
批准号:6902770
-
项目类别:
-
资助金额:$18.61万
-
财政年份:2005
-
负责人:PAUL WHITEAKER
-
依托单位:
Immunochemical Protocols for Nicotinic Receptors
-
批准号:7031028
-
项目类别:
-
资助金额:$21.82万
-
财政年份:2005
-
负责人:PAUL WHITEAKER
-
依托单位:
Alpha-Conotoxin MII: A Selective Nicotinic Receptor Probe
-
批准号:7317703
-
项目类别:
-
资助金额:$35.18万
-
财政年份:1999
-
负责人:PAUL WHITEAKER
-
依托单位:
Alpha-Conotoxin MII: A Selective Nicotinic Receptor Probe
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批准号:7891168
-
项目类别:
-
资助金额:$35.66万
-
财政年份:1999
-
负责人:PAUL WHITEAKER
-
依托单位:
Alpha-Conotoxin MII: A Selective Nicotinic Receptor Probe
-
批准号:7681686
-
项目类别:
-
资助金额:$35.06万
-
财政年份:1999
-
负责人:PAUL WHITEAKER
-
依托单位:
海外基金