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Differential purinergic signaling in bladder sensory neurons of naive and bladder-inflamed mice.

ABSTRACT: This study explored purinergic signaling in lumbosacral (LS) and thoracolumbar (TL) dorsal root ganglion neurons innervating the urinary bladder. In naïve mice, a greater proportion of LS (93%) than that of TL (77%) bladder neurons responded to purinergic agonists. Three types of purinergic currents were identified: 'sustained' (homomeric P2X2) currents were detected only in LS neurons, rapidly activating, 'slow' deactivating (heteromeric P2X2/3) currents predominated in both LS and TL neurons, and 'fast' activating/de-activating (homomeric P2X3) currents were detected only in TL neurons. Relative to TL bladder neurons, slow current density was greater in LS neurons, which also had a more negative action potential threshold and generated more action potentials in response to purinergic agonists (suggesting greater excitability of LS neurons). Single cell nested PCR documented P2X2 and P2X3 subunit expression in both TL and LS bladder neurons. Relative to saline treatment, bladder wall thickness and weight increased after cyclophosphamide (CYP) treatment. Both LS and TL neuron excitability increased (rheobase was decreased and responses to purinergic agonists increased) after CYP treatment. The proportion of sustained currents in LS bladder neurons increased fourfold after CYP bladder inflammation. Although proportions of slow and fast purinergic currents in TL neurons were unchanged by CYP treatment, the fast current density was greater than in saline-treated mice. These results in mouse, as previously described in rat, reveal differential purinergic signaling in TL and LS bladder neurons. The predominant currents and significant changes after inflammation, however, occur in different ganglia/sensory pathways in mouse and rat.

SUBMITTER: Chen X

PROVIDER: S-EPMC2861438 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Differential purinergic signaling in bladder sensory neurons of naïve and bladder-inflamed mice.

Chen Xiaowei X Gebhart G F GF

Pain 20091231 3

This study explored purinergic signaling in lumbosacral (LS) and thoracolumbar (TL) dorsal root ganglion neurons innervating the urinary bladder. In naïve mice, a greater proportion of LS (93%) than that of TL (77%) bladder neurons responded to purinergic agonists. Three types of purinergic currents were identified: 'sustained' (homomeric P2X2) currents were detected only in LS neurons, rapidly activating, 'slow' deactivating (heteromeric P2X2/3) currents predominated in both LS and TL neurons, ...[more]

PMID: 20045252

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Project description:Gastric cancer (GC) is the one of the most prevalent cancers and one of the leading causes of cancer-induced deaths. Previously, we found that the expression of purinergic P2Y2 receptor (P2Y2R) is increased in GC samples as compared to adjacent healthy mucosa taken from GC-diagnosed patients. In this work, we studied in detail purinergic signaling in the gastric adenocarcinoma-derived cell lines: AGS, MKN-45, and MKN-74, and compared them to a nontumoral epithelial cell line: GES-1. In GC-derived cells, we detected the expression of several purinergic receptors, and found important differences as compared to GES-1 cells. Functional studies revealed a strong contribution of P2Y2Rs in intracellular calcium increases, elicited by adenosine-triphosphate (ATP), uridine-triphosphate (UTP), and the P2Y2R agonist MRS2768. Responses were preserved in the absence of extracellular calcium and inhibited by P2Y2R antagonists. In GES-1 cells, ATP and UTP induced similar responses and the combination of P2X and P2Y receptor antagonists was able to block them. Proliferation studies showed that ATP regulates AGS and MKN-74 cells in a biphasic manner, increasing cell proliferation at 10-100 μM, but inhibiting at 300 μM ATP. On the other hand, 1-300 μM UTP, a P2Y2R agonist, increased concentration-dependent cell proliferation. The effects of UTP and ATP were prevented by both wide-range and specific purinergic antagonists. In contrast, in GES-1 cells ATP only decreased cell proliferation in a concentration-dependent manner, and UTP had no effect. Notably, the isolated application of purinergic antagonists was sufficient to change the basal proliferation of AGS cells, indicating that nucleotides released by the cells can act as paracrine/autocrine signals. Finally, in tumor-derived biopsies, we found an increase of P2Y2R and a decrease in P2X4R expression; however, we found high variability between seven different biopsies and their respective adjacent healthy gastric mucosa. Even so, we found a correlation between the expression levels of P2Y2R and P2X4R and survival rates of GC patients. Taken together, these results demonstrate the involvement of different purinergic receptors and signaling in GC, and the pattern of expression changes in tumoral cells, and this change likely directs ATP and nucleotide signaling from antiproliferative effects in healthy tissues to proliferative effects in cancer.

Dataset Information

Differential purinergic signaling in bladder sensory neurons of naive and bladder-inflamed mice.

Publications

Differential purinergic signaling in bladder sensory neurons of naïve and bladder-inflamed mice.

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