低渗透压对大鼠三叉神经节神经元ATP-激活电流的抑制作用
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摘要
本实验应用全细胞膜片钳技术,在大鼠三叉神经节神经元上探讨低渗透压对ATP-激活电流的调制作用。结果显示:(1)大部分受检细胞(80.90%)对外加ATP敏感,产生一具有浓度依赖性的内向电流,且该电流可以被P2X受体拮抗剂PPADS所阻断。(2)预加低渗溶液(220 mOsm,260 mOsm,300 mOsm),对IATP产生抑制作用,该抑制作用呈可逆性,渗透压依赖性和非电压依赖性。(3)在低渗透压(260mOsm)环境下,ATP-激活电流的浓度反应曲线明显下移;阈值和最大反应浓度不变,EC50为1.19×10-4M,与单独加ATP时的1.33×10-4M基本一致;而最大反应浓度时的ATP电流幅值减小了25.26±2.41%(n=6)。(4)低渗透压对IATP的抑制作用可被TRPV4(transient receptor potential vanilloid 4)受体激动剂4ɑ-PDD(4ɑ-phorbol 12,13-didecanoate)增强,并可被TRPV4受体非特异性阻断剂钌红(ruthemium red, RR)阻断。(5)在细胞外液中加入forskolin或8-Br-cAMP预孵育,可以部分翻转低渗对ATP-激活电流的抑制作用,而H89预孵育则不影响低渗对IATP的影响。以上结果表明,低渗透压作用于TRPV4受体,可能通过直接抑制cAMP的生成而抑制P2X受体介导的电流,从而发挥对ATP激活电流的抑制作用。
This experiment aimed to investigate the modulation of hypotonicity on ATP-activated currents (IATP) in primary sensory neurons. Whole cell-patch clamp recording was performed on cultured SD rat trigeminal ganglion (TG) neurons. (1) The majority of neurons examined (80.90%) were sensitive to ATP (10-5~10-3M), ATP activated an inward currents in a concentration-dependent manner, and IATP were blocked by PPADS(pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid, an antagonist of the P2X receptor. (2)When Hypotonicity(220 mOsm, 260 mOsm, 300 mOsm)was preapplied extracellularly, it reduced ATP-activated currents (IATP) significantly. This inhibitory effect was reversible, osmosis-dependent, and voltage-independent. (3) The concentration-response curves for ATP with and without preapplication of hypotonicity showed that preapplication of hypotonicity shifted the curve downward; maximal amplitude of IATP with hypotonicity decreased by 25.26±2.41%, while the threshold value remained unchanged; the EC50 value of the two curves were very close(1.19×10-4M vs 1.33×10-4M). (4) This inhibitory effect was increased by 4ɑ-PDD, a selective TRPV4 receptor agonist, and was reversed by ruthenium red (RR), a nonselective TRPV4 receptor antagonist, suggesting that the inhibition is mediated via TRPV4 receptor. (5) Preapplication of forskolin or 8-Br-cAMP partly reversed the inhibition of IATP by hypotonicity, whereas preapplication of H89 had not effect on it. These results suggested that hypotonicity inhibited ATP-actived currents via TRPV4 receptor, which was mediated partly by reducing cAMP concentration directly rather than by PKA and downstream process.
This experiment aimed to investigate the modulation of hypotonicity on ATP-activated currents (IATP) in primary sensory neurons. Whole cell-patch clamp recording was performed on cultured SD rat trigeminal ganglion (TG) neurons. (1) The majority of neurons examined (80.90%) were sensitive to ATP (10-5~10-3M), ATP activated an inward currents in a concentration-dependent manner, and IATP were blocked by PPADS(pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid, an antagonist of the P2X receptor. (2)When Hypotonicity(220 mOsm, 260 mOsm, 300 mOsm)was preapplied extracellularly, it reduced ATP-activated currents (IATP) significantly. This inhibitory effect was reversible, osmosis-dependent, and voltage-independent. (3) The concentration-response curves for ATP with and without preapplication of hypotonicity showed that preapplication of hypotonicity shifted the curve downward; maximal amplitude of IATP with hypotonicity decreased by 25.26±2.41%, while the threshold value remained unchanged; the EC50 value of the two curves were very close(1.19×10-4M vs 1.33×10-4M). (4) This inhibitory effect was increased by 4ɑ-PDD, a selective TRPV4 receptor agonist, and was reversed by ruthenium red (RR), a nonselective TRPV4 receptor antagonist, suggesting that the inhibition is mediated via TRPV4 receptor. (5) Preapplication of forskolin or 8-Br-cAMP partly reversed the inhibition of IATP by hypotonicity, whereas preapplication of H89 had not effect on it. These results suggested that hypotonicity inhibited ATP-actived currents via TRPV4 receptor, which was mediated partly by reducing cAMP concentration directly rather than by PKA and downstream process.
引文
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9. Feng Xu, Eisaku Satoh., Protein kinasa C-mediated Ca2+ entry in HEK293 cells transiently expressing human TRPV4, British J. of Pharmac, 2003(104) :413-421
10. Watanabe H, Davis JB, et al, Activation of TRPV4 channels (hVRL-2/mTRP12) by phorbol derivatives. J Biol Chem, 2002, (277): 13569–13577.
11. Xiaochong G, Ling W, et al. Temperature-modulated Diversity of TRPV4 Channel Gating. J Biological chemistry, 2003, (278): 27129–27137.
12. Yanlin Jia, Xin Wang, et al. Functional TRPV4 channels are expressed in humanairway smooth muscle cells, Am J Physiol Lung Cell Mol Physiol., 2004, (287): 272–278.
13. Srihasam Lakshmi, Preeti G. et al, Co-activation of P2Y2 receptor and TRPV channel by ATP: implications for ATP induced pain, Cellular and Molecular Neurobiology,2005, 25(5):819-832
14. Chizh, B. A., Illes, P. P2X receptors and nociception. Pharmacol. Rev. 2001 (53):553–568
15. M.J. Wang., S.H. Xiong., Z.W. Li.. Neurokinin B potentiates ATP-activated currents in rat DRG neuron. Brain Res. 2001(923):157-162
16. Dunn, P.P., Zhong, Y., Brunstock, G., et al, P2X receptors in peripheral neurons. Progress in Neurobiology. 2001(65) :107-134
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22. Baruch Minke, Boaz Cook, TRP Channel Proteins and Signal Transduction, Physiol Rev, 2002(10):429-472
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24. Colbert, H. A., Smith, T. L.et al. Osm-9, a novel protein with structural similarity to channels, is required for olfaction, mechanosensation and olfactory adaptation in Caenorhabditis elegans. J. Neurosci, 1997, (17): 8259– 8269.
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27. Watanabe H, Vriens J, et al, Modulation of TRPV4 gating by intra- and extracellular Ca2+. Cell Calcium, 2003, (33): 489–495.
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4. Montell C, Rubin GM. Molecular characterization of the Drosophilatrp locus:a putative integral membrane protein required for phototransduction. Neuron, 1989(2):1313-1323
5. Ali Deniz Gu¨ler, Hyosang Lee, Tohko Iida, Heat-evoked activation of the ion channel, TRPV4, The Journal of Neuroscience, 2002, 22(15):6408–6414
6. Nicole A, Olayinka A. D, et al, Transient receptor potential vanilloid 4 is essential in chemotherapy-induced neuropathic pain in the Rat. J Neuroscience, 2004, 24(18):4444–4452
7. Caterina, M. J., Rosen, T. A. et al. A capsaicin receptor homologue with a high threshold for noxious heat. Nature, 1999, (398):436–441.
8. Okada, T. et al. Molecular cloning and functional characterization of a novel receptor-activated TRP Ca2+ channel from mouse brain. J. Biol. Chem., 1998, (273):10279–10287.
9. Feng Xu, Eisaku Satoh., Protein kinasa C-mediated Ca2+ entry in HEK293 cells transiently expressing human TRPV4, British J. of Pharmac, 2003(104) :413-421
10. Watanabe H, Davis JB, et al, Activation of TRPV4 channels (hVRL-2/mTRP12) by phorbol derivatives. J Biol Chem, 2002, (277): 13569–13577.
11. Xiaochong G, Ling W, et al. Temperature-modulated Diversity of TRPV4 Channel Gating. J Biological chemistry, 2003, (278): 27129–27137.
12. Yanlin Jia, Xin Wang, et al. Functional TRPV4 channels are expressed in humanairway smooth muscle cells, Am J Physiol Lung Cell Mol Physiol., 2004, (287): 272–278.
13. Srihasam Lakshmi, Preeti G. et al, Co-activation of P2Y2 receptor and TRPV channel by ATP: implications for ATP induced pain, Cellular and Molecular Neurobiology,2005, 25(5):819-832
14. Chizh, B. A., Illes, P. P2X receptors and nociception. Pharmacol. Rev. 2001 (53):553–568
15. M.J. Wang., S.H. Xiong., Z.W. Li.. Neurokinin B potentiates ATP-activated currents in rat DRG neuron. Brain Res. 2001(923):157-162
16. Dunn, P.P., Zhong, Y., Brunstock, G., et al, P2X receptors in peripheral neurons. Progress in Neurobiology. 2001(65) :107-134
17. H.Z., Z.W.LI, substance P potentiates ATP-activated currents in rat primary sensory neurons, Brain Res.1996(739):163-168
18. Cook, S.M., et al, Desensitization, recovery and Ca2+-dependent modulation of ATP-gated P2X receptors in nociceptors. Neuropharmacology 1997,(36):1303- 1308
19. Kennedy C, Assis TS, et al. Crossing the pain barrier: P2 receptors as targets for novel analgesics. J Physiol, 2003(553):683-694
20. B.P. Bean. ATP-activated channels in rat and bullfrog sensory neurons: concentration dependence and kinetics. J. Neurosci. 1990(10):1-10
21. Minke B, Wu C, Pak WL. Induction of photoreceptor voltage noise in the dark in Drosophila mutant. Nature, 1975(258): 84-87
22. Baruch Minke, Boaz Cook, TRP Channel Proteins and Signal Transduction, Physiol Rev, 2002(10):429-472
23. Guler A, Lee H,Iida T,et al. Heat evoke activation of the ion channel,TRPV4.J Neurosci,2002(22):6408-6414
24. Colbert, H. A., Smith, T. L.et al. Osm-9, a novel protein with structural similarity to channels, is required for olfaction, mechanosensation and olfactory adaptation in Caenorhabditis elegans. J. Neurosci, 1997, (17): 8259– 8269.
25. Nilius B, Droogmans G, et al. TRP channels in endothelium: solving the calcium entry puzzle? Endothelium, 2003, (10): 5–15.
26. Walker, RG, Willingham, AT. et al. A Drosophila mechanosensory transduction channel.Science, 2000, (287):2229–2234.
27. Watanabe H, Vriens J, et al, Modulation of TRPV4 gating by intra- and extracellular Ca2+. Cell Calcium, 2003, (33): 489–495.
28. Szallasi A, Szabo T, et al, Regulation of a TRP channel by tyrosine phosphorylation: Src family kinase-dependent phosphorylation of TRPV4 on Y253 mediates its response to hypotonic stress. J Biol Chem, 2003, (278):11520–11527.
1. Ali D, Hyosang L, et al. Heat-Evoked Activation of the Ion Channel, TRPV4 . J Neuroscie, 2002, (22): 6408–6414.
2. Altamirano, J., Brodwick, M. S. et al. Regulatory volume decrease and intracellularCa2+ in murine neuroblastoma cells studied with fluorescent probes. J. Gen. Physiol, 1998,( 112):145–160.
3. Baruch Minke, Boaz Cook, et al. TRP Channel Proteins and Signal Transduction, Physiol Rev, 2002, (10):429-472.
4. Boulay, G. et al. Cloning and expression of a novel mammalian homologue of Drosophila transient receptor potential (TRP) involved in calcium entry secondary to activation of receptors coupled the Gq class of G protein. J. Biol. Chem, 1997, (272):29672–29680.
5. Caterina, M. et al.The capsaicin receptor: a heat-activated ion channel in the pain pathway, 1997, (389): 816–824
6. Caterina, M. J., Rosen, T. A. et al. A capsaicin receptor homologuewith a high threshold for noxious heat. Nature, 1999, (398):436–441.
7. Christensen, O. et al, Mediation of cell volume regulation by Ca2+ influx through stretch- activated channels. Nature, 1987, (330):66–68.
8. Colbert, H. A., Smith, T. L.et al. Osm-9, a novel protein with structural similarity to channels, is required for olfaction, mechanosensation and olfactory adaptation inCaenorhabditis elegans. J. Neurosci, 1997, (17):8259–8269.
9. Feng X, Eisaku S, et al. Protein kinase C-mediated Ca2t transiently expressing human TRPV4. J Pharmacology, 2003, (140):413–421.
10. Guler A, Lee H, et al. Heat evokes activation of the ion channel, TRPV4. J Neurosci, 2002 (22):6408-6414.
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