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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.

总结