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Optical control of neuromodulatory GPCRs

神经调节 GPCR 的光学控制

基本信息

批准号：
10012228
负责人：
Ehud Isacoff
金额：
$ 326.39万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10012228
关键词：
AMPA Receptors Adrenergic Agents Agonist Arrestins Atlases Attention Axon Behavior Behavioral Binding Binding Sites Brain region Cells Chemicals Chemistry Cognition Communities Corpus striatum structure Coupled Coupling DRD2 gene Dendrites Desire for food Disease Dopamine Dopamine Receptor Electron Transport Complex III Electrophysiology (science)Epitopes Equilibrium Family Financial compensation G-Protein-Coupled Receptors GABA-B Receptor GTP-Binding Proteins Gene Delivery Genes Glutamate Receptor Goals Histocytochemistry Image Immunologic Tests Injections Knock-out Label Lead Learning Length Ligand Binding Ligand Binding Domain Ligands Light Location Locomotion Membrane Metabotropic Glutamate Receptors Mood Disorders Motor Mus Neuromodulator Neurons Neuropsychology Neurosciences Optics Pathway interactions Pattern Pharmaceutical Preparations Pharmacology Physiological Play Process Receptor Cell Rewards Role Schizophrenia Signal Transduction Sleep Slice Specificity System Testing Time Transgenic Animals Validation Viral Work adeno-associated viral vector approach avoidance behavior brain behavior cell type cholinergic designer receptors exclusively activated by designer drugs extracellular fluorophore genetic manipulation in vivo insight knockout gene motor control neuroregulation novel strategies operation optogenetics protein biomarkers psychologic receptor receptor function remote control spatiotemporal stoichiometry subcellular targeting success tool vector

项目摘要

SUMMARY/ABSTRACT A major goal of neuroscience is to understand how neuromodulatory systems regulate core processes of brain and behavior, from motor function and learning to reward, aversion, attention, and sleep. These systems go awry in schizophrenia and disorders of mood, motor control and cognition. Treatment for these conditions often turns to pharmacological manipulation of neuromodulators and their receptors. Understanding of neuromodulatory circuits has advanced considerably thanks to optogenetics and chemogenetics. But neuromodulation is difficult to crack. A major obstacle is that a single neuromodulator may play many diverse roles because it has multiple receptors, with different functions in different cell locations and different cells within a circuit. Unfortunately, drugs and genetic manipulations cannot typically be targeted or controlled with sufficient spatio-temporal precision to unravel these different functions. We are developing two approaches that provide the needed precision by controlling native, full-length neuromodulatory receptors with photoswitchable tethered ligands (PTLs). Preliminary Iwork demonstrates feasibility of both approaches as applied to two core neuromodulatory receptor families: metabotropic glutamate receptors (mGluRs) and dopamine receptors (DARs). In this proposal, we optimize and expands an approach in which we directly attach PTLs to a specific receptor subtype and develop a new approach that does not touch those receptors, but deliver the PTL to them on a membrane anchor. Because the membrane anchor can be targeted to specific locations within the cell, it can selectively control receptors only at that location, and it can use either broad ligands (which hit all local receptors of that type) or highly selective ligands (to control only one subtype at a time). The tools will be demonstrated in mice and provided to the community as gene delivery vectors, PTLs and transgenic animal lines.

总结/摘要神经科学的一个主要目标是了解神经调节系统如何调节大脑的核心过程和行为，从运动功能和学习到奖励，厌恶，注意力和睡眠。这些系统在精神分裂症和情绪、运动控制和认知障碍中出现偏差。这些疾病的治疗通常转向神经调质及其受体的药理学操作。了解由于光遗传学和化学遗传学，神经调节回路已经有了相当大的进步。但神经调节很难破解一个主要的障碍是一个单一的神经调质可能发挥许多不同的作用，因为它有多种受体，在不同的细胞位置和不同的细胞中具有不同的功能，在一个电路中。不幸的是，药物和基因操作通常不能被靶向或控制，足够的时空精度来解开这些不同的功能。我们正在开发两种方法通过控制天然的全长神经调节受体来提供所需的精确度，光可转换的栓系配体（PTL）。初步工作证明了这两种方法的可行性，应用于两个核心神经调节受体家族：代谢型谷氨酸受体（mGluRs）和多巴胺受体（DARs）。在这项提案中，我们优化和扩展了一种方法，将PTL连接到特定的受体亚型上，并开发出一种不接触这些受体的新方法，而是在膜锚上将PTL递送给它们。因为膜锚可以靶向特定的在细胞内的位置，它可以选择性地控制受体只在该位置，它可以使用或广泛的配体（其击中该类型的所有局部受体）或高选择性配体（以在一个时间点上仅控制一种亚型）。时间）。这些工具将在小鼠中进行演示，并作为基因传递载体（PTL）提供给社区。和转基因动物品系。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cell specific photoswitchable agonist for reversible control of endogenous dopamine receptors.

DOI：
10.1038/s41467-021-25003-w
发表时间：
2021-08-06
期刊：
Nature communications
影响因子：
16.6
作者：
Donthamsetti P;Winter N;Hoagland A;Stanley C;Visel M;Lammel S;Trauner D;Isacoff E
通讯作者：
Isacoff E

Selective Photoswitchable Allosteric Agonist of a G Protein-Coupled Receptor.

DOI：
10.1021/jacs.1c02586
发表时间：
2021-06-23
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Donthamsetti P;Konrad DB;Hetzler B;Fu Z;Trauner D;Isacoff EY
通讯作者：
Isacoff EY

Mesoaccumbal Dopamine Heterogeneity: What Do Dopamine Firing and Release Have to Do with It?

DOI：
10.1146/annurev-neuro-110920-011929
发表时间：
2022-07-08
期刊：
Annual review of neuroscience
影响因子：
13.9
作者：
通讯作者：

Homo- and hetero-dimeric subunit interactions set affinity and efficacy in metabotropic glutamate receptors.

DOI：
10.1038/s41467-023-44013-4
发表时间：
2023-12-13
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Habrian, Chris;Latorraca, Naomi;Fu, Zhu;Isacoff, Ehud Y.
通讯作者：
Isacoff, Ehud Y.

Domain coupling in activation of a family C GPCR.

C 族 GPCR 激活中的域偶联。

DOI：
10.1101/2024.02.28.582567
发表时间：
2024
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Latorraca,NaomiR;Sabaat,Sam;Habrian,Chris;Bleier,Julia;Stanley,Cherise;Marqusee,Susan;Isacoff,EhudY
通讯作者：
Isacoff,EhudY