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.
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.
|Zhang, Hong-Hong; Hu, Ji; Zhou, You-Lang et al. (2013) Promoted interaction of nuclear factor-?B with demethylated cystathionine-?-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|
|Huang, Li-Yen M; Gu, Yanping; Chen, Yong (2013) Communication between neuronal somata and satellite glial cells in sensory ganglia. Glia 61:1571-81|
|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|
|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|
|Wang, Congying; Gu, Yanping; Li, Guang-Wen et al. (2007) A critical role of the cAMP sensor Epac in switching protein kinase signalling in prostaglandin E2-induced potentiation of P2X3 receptor currents in inflamed rats. J Physiol 584:191-203|
|Wang, Congying; Li, Guang-Wen; Huang, Li-Yen Mae (2007) Prostaglandin E2 potentiation of P2X3 receptor mediated currents in dorsal root ganglion neurons. Mol Pain 3:22|
|Zhang, X; Chen, Y; Wang, C et al. (2007) Neuronal somatic ATP release triggers neuron-satellite glial cell communication in dorsal root ganglia. Proc Natl Acad Sci U S A 104:9864-9|
|Gu, Yanping; Xu, Ya; Li, Guang-Wen et al. (2005) Remote nerve injection of mu opioid receptor adeno-associated viral vector increases antinociception of intrathecal morphine. J Pain 6:447-54|
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