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

Alternative mechanisms of signaling via trimeric G proteins

通过三聚体 G 蛋白传递信号的替代机制

基本信息

批准号：
10374905
负责人：
Mikel Garcia-Marcos
金额：
$ 47.87万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10374905
关键词：
Achievement Adenylate Cyclase Affect Area Binding Binding Proteins Biological Assay Biosensor Brain Brain region Cell physiology Cells Chronic inflammatory pain Coin Communication Complex Coupled Cyclic AMP Cytoplasmic Protein Data Disease Ensure Epilepsy Excitatory Synapse Family G Protein-Coupled Receptor Signaling G-Protein Signaling Pathway G-Protein-Coupled Receptors GTP-Binding Protein Regulators GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins GTPase-Activating Proteins Genetic Goals Grant Guanine Nucleotide Dissociation Inhibitors Guanosine Triphosphate Heterotrimeric GTP-Binding Proteins Human Hydrolysis Hyperalgesia Impact Seizures Impairment In Vitro Inhibitory Synapse Ion Channel Knockout Mice Laboratories Link Maps Mass Spectrum Analysis Mechanics Mediating Mediator of activation protein Molecular Neurons Neuropathy Neurotransmitters Nucleotides Pain Pattern Peripheral Nervous System Pharmacology Physiological Physiology Population Post-Translational Protein Processing Predisposition Process Proteins Public Health RGS Proteins Regulation Reporting Role Seizures Signal Transduction Signaling Protein Site Slice Stimulus Synapses Testing Therapeutic Wild Type Mouse base chronic pain human disease insight member mouse model nervous system disorder neuroregulation neurotransmission novel prototype receptor response spinal nerve posterior root synaptic function

项目摘要

SIGNIFICANCE: Our long-term goal is to discover novel regulatory components of a core mechanism of cellular communication, i.e., signaling via heterotrimeric G proteins (henceforth trimeric G proteins), and to characterize the molecular mechanisms that underlie their involvement in human disease. Our emphasis is on cytoplasmic factors that regulate G protein signaling, which have been (and remain) understudied compared to G protein-coupled receptors (GPCRs), the main activating inputs for trimeric G proteins. During the last grant cycle, we made significant advances in this area by achieving all the originally proposed goals, thereby establishing a new paradigm of G protein regulation. We demonstrated the existence of a family of cytoplasmic activators of G proteins, dissected the structural basis for their molecular activity, and established the consequences of their dysregulation in specific cellular processes and human diseases. The specific goal of this renewal application is to characterize the prototype member of a potential new class of G protein regulators that has been linked to chronic pain and epilepsy. The achievement of our goals would provide deep mechanistic insights into a new paradigm of GPCR-G protein regulation that fine tunes inhibitory neuromodulation, and establish a new framework to devise therapeutic strategies for neurological disorders like chronic pain and epilepsy. BACKGROUND: In the course of a screen of proteins that bind to Gαi subunits of Gα-Gβγ timeric complexes, we identified a protein that regulates G proteins via a unique and novel mechanism. We have coined the term “paradoxical G protein regulator” (PGR) to convey that it upregulates the modulation of some G protein effectors while simultaneously downregulating the modulation of other G protein effectors. Loss of this “PGR” is known to alter GPCR signaling in neurons of the peripheral nervous system and causes chronic pain. It has also been linked to epilepsy. Despite its clear biomedical importance, the molecular mechanism by which this G protein regulator operates, and how it modulates neurotransmission in the brain are completely unknown. SYNOPSIS OF AIMS: Based on compelling preliminary data, we propose that the PGR modulates both Gαi- and Gβγ-dependent signaling without directly affecting the G protein enzymatic activity (i.e., nucleotide binding and/or hydrolysis), and that this novel mechanism fine tunes GPCR signaling in brain neurons to influence seizure susceptibility. In Aim#1 we will dissect how the PGR regulates G proteins at the molecular level by characterizing how it engages physically Gαi and the consequences of this physical engagement on G protein signaling to different effectors. In Aim#2 we will characterize how it regulates GPCR signaling and neurotransmission at the cellular level by using primary cultures of neurons and brain slices from wild-type and KO mice. In Aim#3 we will determine the PGR's role at the physiological level by establishing how it impacts seizure susceptibility using genetically modified mouse models.

意义：我们的长期目标是发现一种新的核心机制的调控成分