权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Kinetics of Ligand Binding in Dopamine D1 Receptor Biased Signaling

多巴胺 D1 受体偏向信号传导中配体结合动力学

基本信息

批准号：
9973218
负责人：
John A Allen
金额：
$ 23.7万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-15 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9973218
关键词：
Acute Adenylate Cyclase Agonist Arrestins Attention Attention deficit hyperactivity disorder Automobile Driving Behavior Binding Biological Assay Biological Availability Brain Brain Diseases Catechols Cell Line Cocaine Corpus striatum structure Cyclic AMP Disease Dopamine Dopamine D1 Receptor Elements Evaluation Exhibits Foundations Future G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Goals Huntington Disease Impaired cognition In Vitro Kinetics Knockout Mice Lead Legal patent Ligand Binding Ligands Locomotion Measurable Mediating Membrane Mental disorders Metabolism Mus Neural Pathways Neuraxis Neurologic Oral Outcome Parkinson Disease Penetration Pharmaceutical Preparations Play Preparation Production Property Receptor Signaling Reporting Research Research Project Grants Rewards Role Schizophrenia Second Messenger Systems Short-Term Memory Signal Transduction Signaling Protein Specificity Structure Substance Use Disorder Testing Therapeutic Translational Research Validation arrestin 2 base beta-arrestin clinical application desensitization design in vivo innovation motor control neurotransmission novel novel drug class novel therapeutics pre-clinical prevent radioligand receptor receptor binding receptor function response side effect therapeutic development

项目摘要

Inadequate dopamine (DA) neurotransmission in brain neural pathways is a pathophysiological underpinning of many disabling neurologic and psychiatric illnesses including substance use disorders, attention deficit hyperactivity disorder and cognitive impairments in schizophrenia. The DA D1 receptor (D1R) is a G protein- coupled receptor (GPCR) identified as playing a central role in motor control, reward, attention and working memory. While activation of the D1R could provide a valuable therapeutic strategy for treating diverse brain disorders, undesirable properties of established catechol ligands have prevented therapeutic development for over 40 years. Our research group recently solved this catechol problem and reported the first non-catechol D1R selective agonists that have unprecedented drug-like properties. Many GPCRs, including the D1R, can signal not only through G proteins, but also via G protein-independent interactions with other signaling proteins including, most prominently, β-arrestins. Unexpectedly, several of the novel non-catechol D1R agonists show biased signaling activity via G proteins, without engagement of β-arrestins. This G protein biased signaling by novel D1R agonists may result in superior activation and/or reduced side effect profiles relative to unbiased D1R agonists, providing the innovative opportunity to fine tune D1R activity for neurotherapeutics. Historically, GPCR ligands have been optimized based on their potency, efficacy and specificity; however, another crucial parameter that impacts receptor signaling is the duration of ligand binding to the receptor (i.e., binding kinetics). We hypothesize that the duration of ligand binding is a key mechanism that determines signaling bias of selective D1R agonists towards G proteins versus β-arrestin signaling. The goal of this research project is to validate and quantify the biased agonist activity of these novel D1R agonists and evaluate if faster ligand-receptor binding kinetics is a mechanism driving biased signaling. Aim 1 will use a combination of approaches including functional D1R signaling assays, competition and kinetic binding assays to define a scale of signaling bias for D1R agonists and the kinetic binding parameters (Koff, Kon) for unbiased and biased agonists. We will then correlate these kinetic binding parameters of agonists to β-arrestin-mediated signaling outcomes of desensitization and internalization. Aim 2 will determine if faster binding kinetics drive non-catechol D1R agonist efficacy in vivo. We will assess kinetic binding parameters (Koff, Kon) for unbiased and biased non-catechol D1R agonists from mouse striatal membranes and compare the functional efficacy of D1R agonists on cocaine-induced locomotor behavior using wildtype and β-arrestin2 knockout mice. This research project will expand our highly limited appreciation of ligand properties and mechanisms governing D1R biased signaling. If we discover that the duration of agonist binding is a mechanism underlying biased D1R signaling, we will provide a defining and measurable ligand property to aid in the design of biased agonists. This project will also validate the relevance and potential usefulness of G protein biased agonism for D1R function.

多巴胺（DA）在脑神经通路中的神经传递不足是神经性痴呆的病理生理基础