Our recent studies of modulation of purinergic receptors (P2XR) in dorsal root ganglion (DRG) neurons show that, after inflammation or nerve injury, the activity of P2X3Rs becomes greatly enhanced The increase derives either from an upregulation of P2X3R expression or an increase in the trafficking of P2X3Rs to the cell membrane. This receptor sensitization contributes to abnormal pain responses in rat pain models. We further show that inflammation changes the modulatory signaling of P2X3Rs. Prostaglandin E2 (PGE2) modulation of P2X3Rs switches from a solely PKA-dependent to both PKA and PKC-dependent signaling as a result of the activation of cAMP-regulated guanine nucleotide exchange protein (Epac). Our focus here is to understand the role that Epac may have in changing P2X3R expression and trafficking. We hypothesize that injury facilitates Epac activation. Interactions among Epac, cytoskeletal proteins and scaffold anchoring protein complexes play critical roles in the modulation of P2X3R activity. In vitro and in vivo approaches will be used to test this hypothesis. We will determine if Epac interacts with P2X3Rs, actin and AKAP in DRGs and if injury changes the interactions. We will further determine if these proteins participate in the modulation of P2X3R-mediated current responses. In addition, we will determine if blocking Epac activity can reduce abnormal pain behaviors in rats. These studies should provide a better understanding of the mechanisms underlying injury-induced P2XR sensitization.

Public Health Relevance

This project is designed to understand how neurons become excessively sensitive to stimuli after injury, a phenomenon contributing to chronic pain conditions. The study will identify proteins that control the sensitization and suggest more effective treatments for severe and chronic pain.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Somatosensory and Chemosensory Systems Study Section (SCS)
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Babcock, Debra J
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University of Texas Medical Br Galveston
Schools of Medicine
United States
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Gu, Yanping; Wang, Congying; Li, Guangwen et al. (2016) EXPRESS: F-actin links Epac-PKC signaling to purinergic P2X3 receptors sensitization in dorsal root ganglia following inflammation. Mol Pain 12:
Gu, Yanping; Li, Guangwen; Chen, Yong et al. (2016) Epac-protein kinase C alpha signaling in purinergic P2X3R-mediated hyperalgesia after inflammation. Pain 157:1541-50
Chen, Yong; Li, Guangwen; Huang, Li-Yen Mae (2015) p38 MAPK mediates glial P2X7R-neuronal P2Y1R inhibitory control of P2X3R expression in dorsal root ganglion neurons. Mol Pain 11:68
Huang, Li-Yen M; Gu, Yanping; Chen, Yong (2013) Communication between neuronal somata and satellite glial cells in sensory ganglia. Glia 61:1571-81
Zhang, Hong-Hong; Hu, Ji; Zhou, You-Lang et al. (2013) Promoted interaction of nuclear factor-κB with demethylated cystathionine-β-synthetase gene contributes to gastric hypersensitivity in diabetic rats. J Neurosci 33:9028-38
Li, Guangwen; Ma, Fei; Gu, Yanping et al. (2013) Analgesic tolerance of opioid agonists in mutant mu-opioid receptors expressed in sensory neurons following intrathecal plasmid gene delivery. Mol Pain 9:63
Chen, Yong; Li, Guangwen; Huang, Li-Yen Mae (2012) P2X7 receptors in satellite glial cells mediate high functional expression of P2X3 receptors in immature dorsal root ganglion neurons. Mol Pain 8:9
Wilkes, Denise; Li, Guangwen; Angeles, Carmina F et al. (2012) A large animal neuropathic pain model in sheep: a strategy for improving the predictability of preclinical models for therapeutic development. J Pain Res 5:415-24
Xu, Guang-Yin; Li, Guangwen; Liu, Ningang et al. (2011) Mechanisms underlying purinergic P2X3 receptor-mediated mechanical allodynia induced in diabetic rats. Mol Pain 7:60
Gu, Yanping; Chen, Yong; Zhang, Xiaofei et al. (2010) Neuronal soma-satellite glial cell interactions in sensory ganglia and the participation of purinergic receptors. Neuron Glia Biol 6:53-62

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