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Mechanisms of cAMP signaling that drive spontaneous activity in nociceptors

驱动伤害感受器自发活动的 cAMP 信号传导机制

基本信息

批准号：
10670321
负责人：
Carmen W. Dessauer
金额：
$ 43.1万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10670321
关键词：
A kinase anchoring protein Action Potentials Acute Address Afferent Neurons Animals Biochemistry C Fiber Cell membrane Cellular biology Central Nervous System Chronic Complex Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Drug Combinations Drug Screening Effectiveness Electrophysiology (science)Exposure to FDA approved Funding Goals Hyperactivity Image Imaging Device In Vitro Injury Joints KRAS2 gene Laboratories Link Lipids MAP Kinase Gene Measures Mediating Membrane Lipids Membrane Potentials Microscopy Modeling Neurons Nociceptors Opioid Opioid Receptor Pain Pathway interactions Peripheral Persistent pain Pharmaceutical Preparations Phosphatidylserines Phosphorylation Phosphorylation Site Proteins RAS inhibition Ras/Raf Rattus Refractory Reinforcing Factor Resistance Rest Role Signal Transduction Spinal Ganglia Spinal cord injury Spinal cord injury patients Stimulus Testing cannabinoid receptor chronic pain chronic pain management drug testing endogenous opioids experimental study in vivo in vivo evaluation nanocluster neurotrophic factor novel painful neuropathy recruit response scaffold severe injury spontaneous pain

项目摘要

Project Summary: Chronic pain caused by injury to the peripheral or central nervous system (neuropathic pain) is notoriously resistant to treatment, while the mechanisms that drive and/or maintain chronic pain remain unclear. We have shown that chronic nociceptor hyperexcitability after severe injury is maintained by cAMP signaling through multiple cAMP effectors, including PKA, EPAC and HCN channels. These pathways are enhanced by AKAP-mediated complex formation with AC and show significant cross-talk with Ras/MAPK signaling. Activation of cAMP- and Ras-mediated pathways initiate at the plasma membrane (PM) and are uniquely sensitive to clustering of lipids within the PM. We have also shown that spinal cord injury reduces AC inhibition by Gαi, resulting in reduced potency of opioids in DRG neurons. This reduced sensitivity can be mimicked in DRG neurons from naïve animals by overnight exposure to neurotrophic factors or by a 5 min, modest depolarization that approaches the firing threshold of DRG neurons after severe injury. Importantly, nociceptor hyperexcitability and reductions in opioid potency, induced by either injury, neurotrophic factors or acute depolarization, can be reversed by inhibition of Ras-dependent signaling or reorganization of lipids in the plasma membrane. We hypothesize that the sustained depolarization that occurs in many injury models drives alterations in PM lipid organization, leading to increased ERK signaling and decreased opioid responses. Release of neurotrophic factors reinforce these pathways and, in conjunction with cAMP signaling, drives nociceptor hyperexcitability and a chronic pain state. To address these hypotheses, we propose three Aims. 1) Determine the mechanism for reduced MOR-Gαi inhibition of AC by C-Raf, 2) Define the mechanism of Ras activation and nociceptor hyperexcitability by depolarization and SCI, and 3) Define functional consequences of interactions among depolarization and cell signaling by cAMP, C-Raf, and ERK. Importantly, our model identifies multiple FDA-approved drugs that could simultaneously enhance endogenous opioid responses and block nociceptor hyperexcitability after severe injury.

项目总结:

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

EPAC1 and EPAC2 promote nociceptor hyperactivity associated with chronic pain after spinal cord injury.

DOI：
10.1016/j.ynpai.2019.100040
发表时间：
2020-01-01
期刊：
Neurobiology of pain (Cambridge, Mass.)
影响因子：
0
作者：
Berkey, Samantha C;Herrera, Juan J;Bavencoffe, Alexis G
通讯作者：
Bavencoffe, Alexis G

Isolated nociceptors reveal multiple specializations for generating irregular ongoing activity associated with ongoing pain.

DOI：
10.1097/j.pain.0000000000001341
发表时间：
2018-11
期刊：
Pain
影响因子：
7.4
作者：
Odem MA;Bavencoffe AG;Cassidy RM;Lopez ER;Tian J;Dessauer CW;Walters ET
通讯作者：
Walters ET

Exaptation and Evolutionary Adaptation in Nociceptor Mechanisms Driving Persistent Pain.

驱动持续性疼痛的伤害感受器机制的外延适应和进化适应。

DOI：
10.1159/000535552
发表时间：
2023
期刊：
Brain, behavior and evolution
影响因子：
0
作者：
Walters,EdgarT
通讯作者：
Walters,EdgarT

Single-cell RNA-sequencing of the brain.

DOI：
10.1186/s40169-017-0150-9
发表时间：
2017-12
期刊：
Clinical and translational medicine
影响因子：
10.6
作者：
Cuevas-Diaz Duran R;Wei H;Wu JQ
通讯作者：
Wu JQ

Interleukin-10 resolves pain hypersensitivity induced by cisplatin by reversing sensory neuron hyperexcitability.

DOI：
10.1097/j.pain.0000000000001921
发表时间：
2020-10
期刊：
Pain
影响因子：
7.4
作者：
Laumet G;Bavencoffe A;Edralin JD;Huo XJ;Walters ET;Dantzer R;Heijnen CJ;Kavelaars A
通讯作者：
Kavelaars A

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Carmen W. Dessauer其他文献

Spatial organization of adenylyl cyclase and its impact on dopamine signaling in neurons

腺苷酸环化酶的空间组织及其对神经元中多巴胺信号传导的影响

DOI：
10.1038/s41467-024-52575-0
发表时间：
2024-09-27
期刊：
Nature Communications
影响因子：
15.700
作者：
Léa Ripoll;Yong Li;Carmen W. Dessauer;Mark von Zastrow
通讯作者：
Mark von Zastrow

Gβγ Activates GIRK2 with Low-Micromolar Affinity with Distinct Activation Pattern Compared to GIRK1/2

DOI：
10.1016/j.bpj.2019.11.1557
发表时间：
2020-02-07
期刊：
Conference abstract
影响因子：
作者：
Daniel Yakubovich;Uri Kahanovitch;Galit Tabak;Tal Keren Raifman;Vladimir Tsemakhovich;Debi Ranjan Tripathy;Carmen W. Dessauer;Joel A. Hirsch;Nathan Dascal
通讯作者：
Nathan Dascal

Preferential Association with Gβγ Over Gα Governs the Activity of a G Protein-Activated K+ Channel

DOI：
10.1016/j.bpj.2011.11.2939
发表时间：
2012-01-31
期刊：
Conference abstract
影响因子：
作者：
Daniel Yakubovich;Shai Berlin;Moran Rubinstein;Uri Kahanovich;Carmen W. Dessauer;Nathan Dascal
通讯作者：
Nathan Dascal