New tools for studying receptor dimers
研究受体二聚体的新工具
基本信息
- 批准号:10430478
- 负责人:
- 金额:$ 21.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-01 至 2024-02-29
- 项目状态:已结题
- 来源:
- 关键词:AffinityAgonistAmino Acid SequenceBehaviorBiologicalBrainBrain regionCell membraneCicatrixClinicCloningColorCommunitiesComplexDataDimerizationDrug ScreeningEndoplasmic ReticulumEvaluationExcisionExhibitsExteinsFamilyFluorescence Resonance Energy TransferFutureG-Protein-Coupled ReceptorsGlutamatesHeterodimerizationHomoHomodimerizationKnowledgeLibrariesLigandsLinkMapsMembraneMembrane ProteinsMetabotropic Glutamate ReceptorsMethodsNeurotransmittersOrangesPathologyPerformancePharmacologyPhysiologyPopulationProblem SolvingProteinsRNA SplicingReceptor SignalingResearchShapesSignal TransductionSirolimusSiteSynaptic TransmissionSystemTailTestingWorkdesigndimerdruggable targetinteinmetabotropic glutamate receptor 2metabotropic glutamate receptor 4notch proteinnovelpre-clinicalreceptorreceptor functionresponseretention ratesensortargeted treatmenttooltrafficking
项目摘要
Abstract
Metabotropic glutamate receptors (mGluRs) are class C G protein coupled receptors that function as dimers.
While mGluRs are known to form homodimers, more recent work has shown that they can also heterodimerize,
but not promiscuously. Because mGluRs exhibit widespread expression in the brain and regulate excitability and
plasticity, they have become candidates as druggable targets for a variety of pathologies. To date however,
excitement generated by preclinical data has not resulted in mGluR-targeting therapies in the clinic, despite a
wealth of available ligands with good selectivity targeting these receptors. Our recent work examining mGluR2/4
heterodimers provides a possible explanation: ligands that are highly efficacious when targeting homodimeric
receptors are often without effect when the same receptor is expressed as a heterodimer with another mGluR.
Further complicating matters, these changes in pharmacological responses observed in mGluR2/4 heterodimers
are not generalizable to all mGluR heterodimers, or even all mGluR2 containing heterodimers. Thus, to
understand how any mGluR ligand will function in the brain, we must examine the pharmacological responses
of each possible heterodimer pair in isolation. But this is complicated because every mGluR can also form
homodimers, so any pair of expressed mGluR will have an unknown propensity to homo- and heterodimerize.
To solve this problem, we have designed a novel dimer composition control system using a combination of ER
retention sequences paired with orthogonal, split inteins, self-excising protein sequences, that will allow
expression of pure populations of nearly wild type mGluR dimers of known composition. This system will be
valuable not only in defining the pharmacological behavior of each dimer pair, but also by providing a broader
and more accurate picture of the effects of mGluR targeting ligands by serving as a platform for broadly scoped
drug screening. Further, this strategy provides a template for the study of other dimerizing membrane proteins.
To this end, we will pursue the following Specific Aims: 1- Determine the performance and limitations of our
novel eukaryotic split-intein system, and 2- Generate and test each mGluR combination with the split-
intein system.
摘要
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 J. Kammermeier其他文献
Determining the Topology of the Acid-Sensing Ion Channel Intracellular Domains
- DOI:
10.1016/j.bpj.2020.11.2112 - 发表时间:
2021-02-12 - 期刊:
- 影响因子:
- 作者:
Tyler A. Couch;Kyle Berger;Dana Kneisley;Matthew L. Rook;Tyler W. McCullock;Paul J. Kammermeier;David M. MacLean - 通讯作者:
David M. MacLean
Investigating the Heteromerization of Metabotropic Glutamate Receptors using a Novel Single Molecule Imaging Method
- DOI:
10.1016/j.bpj.2017.11.2903 - 发表时间:
2018-02-02 - 期刊:
- 影响因子:
- 作者:
Alexander L. Van Slyke;Avtar Singth;Nitya Deshmukh;Paul J. Kammermeier;Warren R. Zipfel - 通讯作者:
Warren R. Zipfel
Paul J. Kammermeier的其他文献
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{{ truncateString('Paul J. Kammermeier', 18)}}的其他基金
A novel system for controlling dimeric receptor composition to discover unique heterodimer pharmacology
控制二聚体受体组成的新系统,以发现独特的异二聚体药理学
- 批准号:
10735066 - 财政年份:2023
- 资助金额:
$ 21.48万 - 项目类别:
Tools for studying the regulation of Homer protein splicing
研究荷马蛋白剪接调节的工具
- 批准号:
10349911 - 财政年份:2021
- 资助金额:
$ 21.48万 - 项目类别:
Functional and Pharmacological Implications of mGluR Heteromerization
mGluR 异聚化的功能和药理学意义
- 批准号:
8643265 - 财政年份:2012
- 资助金额:
$ 21.48万 - 项目类别:
Functional and Pharmacological Implications of mGluR Heteromerization
mGluR 异聚化的功能和药理学意义
- 批准号:
8452668 - 财政年份:2012
- 资助金额:
$ 21.48万 - 项目类别:
Functional and Pharmacological Implications of mGluR Heteromerization
mGluR 异聚化的功能和药理学意义
- 批准号:
9036403 - 财政年份:2012
- 资助金额:
$ 21.48万 - 项目类别:
Functional and Pharmacological Implications of mGluR Heteromerization
mGluR 异聚化的功能和药理学意义
- 批准号:
8829302 - 财政年份:2012
- 资助金额:
$ 21.48万 - 项目类别:
Functional and Pharmacological Implications of mGluR Heteromerization
mGluR 异聚化的功能和药理学意义
- 批准号:
8270968 - 财政年份:2012
- 资助金额:
$ 21.48万 - 项目类别:
Functional and Pharmacological Implications of mGluR Heteromerization
mGluR 异聚化的功能和药理学意义
- 批准号:
8726532 - 财政年份:2012
- 资助金额:
$ 21.48万 - 项目类别:
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