Novel mechanism on subpopulation-dependent biased GPCR signaling in neurons

神经元亚群依赖性偏向 GPCR 信号传导的新机制

基本信息

批准号：
9767795
负责人：
YANG K XIANG
金额：
$ 27.63万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9767795
关键词：
Adrenergic Agents Adrenergic Receptor Adrenergic beta-Antagonists Agonist Alprenolol Alzheimer&apos s Disease Anxiety Anxiety Disorders Asthma Attention Attention deficit hyperactivity disorder Biochemical Biosensor Cardiovascular Diseases Cell membrane Chronic Obstructive Airway Disease Clinical Crystallography Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Dendrites Disease Drug Receptors Drug Targeting Explosion Family Fluorescence Resonance Energy Transfer Fractionation G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Glaucoma Heart failure Hippocampus (Brain)Hypertension Image Individual Ion Channel L-Type Calcium Channels Learning Ligands Link Mammalian Cell Memory Mental Depression Metabolic syndrome Modification Nature Neuraxis Neurons Norepinephrine Peripheral Phosphorylation Phosphotransferases Physiological Play Post-Traumatic Stress Disorders Psyche structure Resolution Role Signal Transduction Sympathomimetics Synapses Synaptic plasticity Testing alertness alpha-adrenergic receptor base beta-adrenergic receptor carvedilol cellular imaging clinical application clinically relevant design innovation interest neuronal excitability novel postsynaptic receptor response side effect tool trafficking

项目摘要

Summary Adrenergic receptors (ARs) are a family of prototypical GPCRs linked to neuronal disorders, metabolic syndrome, and cardiovascular diseases. In the CNS, norepinephrine (NE) regulates attention and alertness. The β2AR is emerging as the prevalent postsynaptic NE effector at glutmatergic synapses, where it interacts with AMPAR, NMDAR and L-type Ca2+ channel Cav1.2 to modulate neuronal excitability, synaptic plasticity, and memory and learning. It is clinically relevant to understand NE-linked mental diseases such as depression, attention deficit hyperactivity disorder (ADHD), anxiety disorders (e.g., posttraumatic stress disorder, PTSD) and Alzheimer's disease. While β-blockers are used to treat a variety of peripheral diseases including heart failure, hypertension, glaucoma, asthma, and COPD, their clinical utility is hampered by the side effects including anxiety and depression. Recent explosion of crystallography study of ligand-GPCR interactions, there is still limited understanding on how a specific ligand leads to pleotropic cellular responses (including sides effects) of a GPCR. In this study, we hypothesize that a distinct subpopulation of PKA-phosphorylated β2ARs control LTCC activation in hippocampal neurons, which can be selectively activated by a set of biased ligands. We will test our hypothesis with following specific aims: Aim 1 is to test the hypothesis that β2AR can exist in distinct functional subpopulations in a single mammalian cell. We will use biochemical isolation/fractionation and super-resolution imaging to characterize distinct subcellular distribution of PKA-pβ2AR and GRK-pβ2AR. Aim 2 is to test the hypothesis that PKA-pβ2AR transduce biased signal through selectively modulation of ion channel activity at the plasma membrane (PM). Aim 3 is to test the hypothesis that sympathomimetic β-blockers act as biased ligands that selectively activate PKA-phosphorylated subpopulation of β2AR to activate ion channel at the PM. If successful, these aims will reveal a platform to understand the biased signaling induced by two distinct subpopulations of β2AR, and offering a new avenues for designing more efficacious β-AR drugs with fewer side effects in clinical applications.

概括肾上腺素能受体 (AR) 是与神经元疾病、代谢紊乱相关的典型 GPCR 家族在中枢神经系统中，去甲肾上腺素 (NE) 调节注意力和警觉性。 β2AR 正在成为谷氨酸突触中普遍存在的突触后 NE 效应器，它在其中相互作用与 AMPAR、NMDAR 和 L 型 Ca2+ 通道 Cav1.2 调节神经元兴奋性、突触可塑性、了解 NE 相关的精神疾病（例如，记忆和学习）具有临床意义。抑郁症、注意力缺陷多动障碍 (ADHD)、焦虑症（例如创伤后应激障碍）障碍、创伤后应激障碍（PTSD）和阿尔茨海默氏病，而β受体阻滞剂则用于治疗各种外周疾病。疾病包括心力衰竭、高血压、青光眼、哮喘和慢性阻塞性肺病，其临床用途是最近晶体学研究的爆炸性进展阻碍了这一研究的进展。配体-GPCR 相互作用，对于特定配体如何导致多效性的了解仍然有限 GPCR 的细胞反应（包括副作用）在这项研究中，我们追求一种独特的反应。 PKA 磷酸化 β2AR 亚群控制海马神经元中的 LTCC 激活，这可以被一组有偏向的配体选择性激活我们将通过以下特定目标来检验我们的假设：目标 1 是检验以下假设：β2AR 可以存在于单一的不同功能亚群中。我们将使用生化分离/分级和超分辨率成像来检测哺乳动物细胞。表征 PKA-pβ2AR 和 GRK-pβ2AR 的不同亚细胞分布目的 2 是检验假设。 PKA-pβ2AR 通过选择性调节离子通道活性来转导偏置信号目标 3 是检验拟交感神经 β 受体阻滞剂有偏向性的假设。选择性激活 β2AR 的 PKA 磷酸化亚群以激活离子通道的配体如果成功的话，这些目标将揭示一个平台来理解两个因素引起的偏见信号。 β2AR 的独特亚群，并为设计更有效的 β-AR 药物提供了新途径临床应用中副作用较少。