δ阿片受体的表达和激活对谷氨酸转运蛋白EAAC1的调节
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摘要
谷氨酸转运蛋白在调节突触间隙内的谷氨酸的时空分布上起重要的作用,它防止由于胞外过高的谷氨酸浓度而给细胞带来的毒害作用。兴奋性氨基酸转运蛋白EAAC1是神经元特异性的,它参与调节突触间隙的谷氨酸浓度。阿片受体在大脑中参与谷氨酸能神经系统的调节,但是具体的机制仍需要进行进一步研究。本文报道了在非洲爪蟾卵母细胞中delta阿片受体(DOR)与EAAC1的共表达可以下调EAAC1的功能,而mu阿片受体的共表达并不影响EAAC1的功能。EAAC1由于DOR的表达而导致的下降功能可通过DPDPE激活DOR受体而得到抵消。用生物素标记膜上受体的实验结果显示这种DOR对EAAC1功能的调节并不改变胞内和膜上的EAAC1表达量。从卵母细胞和大鼠海马神经细胞得到的免疫共沉淀和免疫荧光的结果均显示EAAC1和DOR两种蛋白存在共定位,这表明二者之间存在直接的相互作用。与EAAC1功能实验一致的是DPDPE激活DOR会减弱他们之间的相互作用。
我们的结果提示delta阿片受体可以通过蛋白-蛋白间的相互作用来调节EAAC1的功能,而DOR的激活可以释放这种相互作用导致的抑制作用。我们认为这个机制可能在阿片处理后的谷氨酸能神经系统的调节中发挥重要作用。
Glutamate transporters play an essential role in regulating temporal and spatialglutamate concentration in synaptic cleft. The excitatory amino acid carrier 1(EAAC1), which is a neuronal specific transporter, regulates the synaptic glutamateconcentration. Opioid receptors are found to modulate the glutamatergic system inbrain, but the regulatory mechanism remains to be investigated. Here we report thatthe δ-opioid receptor (DOR) co-expressed with EAAC1 in Xenopus oocytes, but notthe μ-opioid receptor, down-regulates EAAC1 function, and that DPDPE stimulationof DOR can counteract the down regulation of the EAAC1-mediated uptake. Resultsfrom co-immunoprecipitation and immunofluorescence microscopy in both oocytesand rat hippocampal neurons indicate co-localization and suggest direct interactionbetween DOR and EAAC1, and this interaction reduce after DOR receptoractivation.
Our results suggest that the delta opioid receptor can modulate EAAC1function by direct protein-protein interaction and that activation of DOR releases theinhibitory interaction. We suggest that this mechanism may be important formodulation of the glutamatergic system after opioid stimulation.
我们的结果提示delta阿片受体可以通过蛋白-蛋白间的相互作用来调节EAAC1的功能,而DOR的激活可以释放这种相互作用导致的抑制作用。我们认为这个机制可能在阿片处理后的谷氨酸能神经系统的调节中发挥重要作用。
Glutamate transporters play an essential role in regulating temporal and spatialglutamate concentration in synaptic cleft. The excitatory amino acid carrier 1(EAAC1), which is a neuronal specific transporter, regulates the synaptic glutamateconcentration. Opioid receptors are found to modulate the glutamatergic system inbrain, but the regulatory mechanism remains to be investigated. Here we report thatthe δ-opioid receptor (DOR) co-expressed with EAAC1 in Xenopus oocytes, but notthe μ-opioid receptor, down-regulates EAAC1 function, and that DPDPE stimulationof DOR can counteract the down regulation of the EAAC1-mediated uptake. Resultsfrom co-immunoprecipitation and immunofluorescence microscopy in both oocytesand rat hippocampal neurons indicate co-localization and suggest direct interactionbetween DOR and EAAC1, and this interaction reduce after DOR receptoractivation.
Our results suggest that the delta opioid receptor can modulate EAAC1function by direct protein-protein interaction and that activation of DOR releases theinhibitory interaction. We suggest that this mechanism may be important formodulation of the glutamatergic system after opioid stimulation.
引文
1. Danbolt, N.C: Glutamate uptake. Prog Neurobiol. (2001) 65, 1-105.
2. Otis, T.S., Kavanaugh, M.P. & Jahr, C.E: Postsynaptic glutamate transport at the climbing fiber purkinje-cell synapse. Science (1997) 277, 1515-1518.
3. Sims, K.D. & Robinson, M.B: Expression patterns and regulation of glutamate transporters in developing and adult nervous system. Crit Rev Neurobiol. (1999) 13, 169-197.
4. Choi, D.W., Maulucci-Gedde, M. & Kriegstein, A.R: Glutamate neurotoxicity in cortical cell culture. J Neurosci. (1987) 7, 357-368.
5. Cougnon, M., Planelles, G., Crowson, M.S., Shull, G.E., Rossier, B.C. & Jaisser, F: The rat distal colon p-ATPase alpha-subunit encodes a ouabain-sensitive H+, K+-ATPase. J Biol Chem. (1996) 271, 7277-7280.
6. Trotti, D., Danbolt, N.C. & Volterra, A: Glutamate transporters are oxidant-vulnerable: A molecular link between oxidative and excitotoxic neurodegeneration. Trends Pharmacol Sci. (1998) 19, 328-334.
7. Levenson, J., Weeber, E., Selcher, J.C., Kategaya, L.S., Sweatt, J.D. & Eskin, A: Long-term potentiation and contextual fear conditioning increase neuronal glutamate uptake. Nat Neurosci. (2002) 5, 155-161.
8. Rothstein, J.D., Martin, L., Levey, A.I., Dykes-Hoberg, M., Jin, L., Wu, D., Nash, N. & Kuncl, R.W: Localization of neuronal and glial glutamate transporters. Neuron (1994) 13, 713-725.
9. He, Y., Janssen, W.G., Rothstein, J.D. & Morrison, J.H: Differential synaptic localization of the glutamate transporter EAAC1 and glutamate receptor subunit GluR2 in the rat hippocampus. J Comp Neurol. (2000) 418, 255-269.
10. Zerangue, N. & Kavanaugh, M.P: Flux coupling in a neuronal glutamate transporter. Nature (1996) 383, 634-637.
11. Wadiche, J.I., Amara, S.G. & Kavanaugh, M.P: Ion fluxes associated with excitatory amino acid transport. Neuron (1995) 15, 721 –728.
12. Slotboom, D.J., Konings, W.N. & Lolkema, J.S: The structure of glutamate transporters shows channel-like features. FEBS Lett. (2001) 492, 183-186.
13. Robbins, T.W. & Everitt, B.J: Drug addiction: bad habits add up. Nature (1999) 398, 567-570.
14. Mansouri, F.A., Motamedi, F., Fathollahi, Y., Atapour, N. & Semnanian, S: Augmentation of LTP induced by primed-bursts tetanic stimulation in hippocampal CA1 area of morphine dependent rats. Brain Res. (1997) 769, 119-124.
15. Mansouri, F.A., Motamedi, F. & Fathollahi, Y: Chronic in vivo morphine administration facilitates primed-bursts-induced long-term potentiation of Schaffer collateral-CA1 synapses in hippocampal slices in vitro. Brain Res. (1999) 815, 419 –423.
16. Pu, L., Bao, G.B., Xu, N.J., Ma, L. & Pei, G: Hippocampal long-term potentiation is reduced by chronic morphine treatment and can be restored by re-exposure to opiates. J Neurosci. (2002) 22, 1914-1921.
17. Dingledine, R., Valentino, R.J., Bostock, E., King, M.E. & Chang, K.J: Down-regulation of delta but not mu opioid receptors in the hippocampal slice associated with loss of physiological response. Life Sci. (1983) 33 (Suppl.1), 333-336.
18. Vlaskovska, M., Schramm, M., Nylander, I., Kasakow, L., You, Z.B., Herrera-Marschitz, M. & Terenius, L: Opioid effects on 45Ca2+ uptake and glutamate release in rat cerebral cortex in primary culture. J Neurochem. (1997) 68, 517-524.
19. Tanaka, E., & North, R.A: Opioid actions on rat anterior cingulate cortex neurons in vitro. J Neursci. (1994) 14, 1106-1113.
20. Vorel, S.R., Liu, X., Haye, R.J., Spector, J.A.& Gardner, E.L:Relapse to cocaine-seeking after hippocampal theta burst stimulation. Science (2001) 292, 1175-1178.
21. Clark, J.A. & Amara, S.G: Amino-acid neurotransmitter transporters -structure, function, and molecular diversity. Bioessays (1993) 15, 323-332.
22. Beckman, M.L. & Quick, M.W: Neurotransmitter transporters: regulators of function and functional regulation. J Membrane Biol. (1998) 164, 1-10.
23. Xu, N.J., Bao, L., Fan, H.P., Bao, G.B., Pu, L., Lu, Y.J., Wu, C.F., Zhang, X. & Pei, G: Morphine Withdrawal Increases Glutamate Uptake and Surface Expression of Glutamate Transporter GLT1 at Hippocampal Synapses. J Neurosci. (2003) 23 (11), 4775– 4784.
24. Mao, J., Sung, B., Ji, R.R. & Lim, G: Chronic morphine induces downregulation of spinal glutamate transporters: implications in morphine tolerance and abnormal pain sensitivity. J Neurosci. (2002) 22, 8312-8323.
25. Vasilets, L.A: Diversity of regulatory phosphorylation of the Na+/K+-ATPase from mammalian kidneys and Xenopus oocytes by protein kinases. Characterisation of the phosphorylation site for PKC. Cell Physiol Biochem. (1997) 7, 1-18.
26. Zhu, Y.N., Fei, J. & Schwarz, W: Expression and transport function of the glutamate transporter EAAC1 in Xenopus oocytes is regulated by syntaxin 1A. J Neurosci Res. (2005) 79 (4), 503-508.
27. Schmalzing, G., Omay, H., Kr?ner, S., Gloor, S., Appelhans, H. & Schwarz, W: Up-regulation of sodium pump activity in Xenopus laevis oocytes by expression of heterologous ?1 subunits of the sodium pump. Biochem J. (1991) 279, 329-336.
28. Solis-Garrido, L.M., Pintado, A.J., Anderes-Mateos, E., Figueron, M., Matute, C. & Montiel, C: Cross-talk between native plasmalemmal Na+/Ca2+ exchanger and inositol 1,4,5-trisphosphate-sensitive Ca2+ internal store in xenopus oocyte J Biol Chem. (2004) 279, 52414-52424.
29. Michael, M.W. & Maria, A: Niflumic and flufenamic acids are potent reversible blockers of Ca2+-Activated Cl-channels in Xenopus oocytes. Mol Pharmacol. (1990) 37, 720-724.
30. Chen, J.G., Liu-Chen, S. & Rudnick, G.: External cysteine residues in the serotonin transporter. Biochemistry (1997) 36, 1479-1486.
31. Grabb, M.C. & Choi, D.W: Ischemic tolerance in murine cortical cell culture: Criticial role for NMDA receptors. J Neurosci. (1999) 19: 1657-1662.
32. Khodorov, B.I: Glutamate-induced deregulation of calcium homeostasis and mitochondrial dysfunction in mammalian central neurones. Prog Biophys Molec Biol. (2004) 86, 279-351.
33. Kanai, Y. & Hediger, M.A: The glutamate and neutral amino acid transporter family: physiological and pharmacological implications. Eur J Pharmacol. (2003) 479, 237-247.
34. Dowd, L.A., Coyle, A.J., Rothstein, J.D., Pritchett, D.B. & Robinson, M.B: Comparison of Na+-dependent glutamate transport activity in synaptosomes, C6 glioma, and xenopus oocytes expressing excitatory amino-acid carrier-1 (EAAC1). Mol Pharmacol. (1996) 49, 465-473.
35. Davis, K.E., Straff, D.J., Weinstein, E.A., Bannermann, P.G., Correale, D.M., Rothstein, J.D. & Robinson, M.B: Multiple signaling pathways regulate cell surface expression and activity of the excitatory amino acid carrier 1 subtype of Glutamate transporter in C6 glioma. J Neurosci. (1998) 18, 2475-2485.
36. Trotti, D., Peng, J.B., Dunlop, J. & Hediger, M.A: Inhibition of the glutamate transporter EAAC1 expressed in Xenopus oocytes by phorbol esters. Brain Res. (2001) 914, 196-203.
37. Gonzalez, M.I., Bannermann, P.G. & Robinson, M.B: Phorbol myristate acetate-dependent interaction of protein kinase Calpha and the neuronal glutamate transporter EAAC1. J Neurosci. (2003) 23, 5589-5593.
38. Lin, C.L.G., Orlov, I., Ruggerio, A.M., Dykes-Hoberg, M., Lee, A., Jack-son, M. & Rothstein, J.D: Modulation of the neuronal glutamate transporter EAAC1 by an interacting protein GTRAP3–18. Nature (2001) 410, 84–88.
39. Rothstein, J.D., Dykes-Hoberg, M., Pardo, C.A., Baristol, L.A., Jin, L., Kuncl, R.W., Kanai, Y., Hediger, M.A., Wang, Y., Schielke, J.P. & Welty, D.F: Knockout of glutamate transporters reveals a major role for astroglial transport in excitoxicity and clearence of ghitamate. neuron (1996) 18 (3), 675-686.
40. Zhang, G., Raol, Y.S., Hsu, F.C. & Brooks-Kayal, A.R: Long-term alterations in glutamate receptor and transporter expression following early-life seizures are associated with increased seizure susceptibility. J Neurochem (2004) 88, 91-101.
41. Nakagawa, T., Ozawa, T., Shige, K., Yamamoto, R., Minami, M., Satoh, M: Inhibition of morphine tolerance and dependence by MS-153, a glutamate transporter activator. Eur J Pharmacol. (2001) 419 (1), 39-45.
42. Cheng, P.Y., Svingos, A.L., Wang, H., Clarke, C.L., Jenab, S., Beczkowska, I.W., Inturrisi, C.E. &Pickel, V.M: Ultrastructural immunolabeling shows prominent presynaptic vesicular localization of delta-opioid receptor within both enkephalin-and nonenkephalin-containing axon terminals in the superficial layers of the rat cervical spinal cord. J Neurosci. (1995) 15, 5976-5988.
43. Commons, K.G. & Milner, T.A: Localization of delta opioid receptor immunoreactivity in interneurons and pyramidal cells in the rat hippocampus. J Comp Neurol. (1997) 381, 373-387.
44. Tao, F., Liaw, W.J., Zhang, B., Yaster, M., Rothstein, J.D. & Tao, Y.X: Evidence of neuronal excitatory amino acid carrier 1 expression in rat dorsal root ganglion neurons and their central terminals. Neuroscience (2004) 123, 1045-1051.
45. Guo, M., Xu, N.J., Li, Y.T., Yang, J.Y., Wu, C.F. & Pei, G: Morphine modulates glutamate release in the hippocampal CA1 area in mice. Neurosci Lett. (2005) 381, 12-15.
46. Chen, Y., Mestek, A., Liu, J., Yu, L: Molecular cloning of a rat kappa opioid receptor reveals sequence similarities to the mu and delta opioid receptors. Biochem J. (1993) 295, 625-628.
47. Finn, A.K. & Whistler, J.L: Endocytosis of the mu opioid receptor reduces tolerance and a cellular hallmark of opiate withdrawal. Neuron (2001) 32, 829-839.
48. Whistler, J.L., Enquist, J., Marley, A., Fong, J., Gladher, F., Tsuruda, P., Murray, S.R. & Von Zastrow, M: Modulation of postendocytic sorting of G protein-coupled receptors. Science (2002) 297, 615-620.
49. Waldhoer, M., Bartlett, S.E. & Whistler, J.L: Opioid receptors. Annu Rev Biochem. (2004) 27, 953-990.
50. Bao, L., Jin, S.X., Zhang ,C., Wang, L.H., Xu, Z.Z., Zhang, F.X., Wang, L.C., Ning, F.S., Cai, H.J., Guan ,J.S., Xiao, H.S., Xu, Z.Q., He, C., Hokfelt, T., Zhou, Z. & Zhang, X: Activation of delta opioid receptors induces receptor insertion and neuropeptide secretion. Neuron (2003) 37(1), 121-133.
51. Sora, I., Funada, M. & Uhl, G.R: The mu-opioid receptor is necessary for [D-Pen2,D-Pen5]enkephalin-induced analgesia. Eur J Pharmacol. (1997) 324, R1-2.
52. Zhang, J., Gibney, G.T., Zhao, P. & Xia, Y: Neuroprotective role of d-opioid receptors in cortical neurons. Am J Physiol Cell Physiol. (2002) 282, 1225-1234.
2. Otis, T.S., Kavanaugh, M.P. & Jahr, C.E: Postsynaptic glutamate transport at the climbing fiber purkinje-cell synapse. Science (1997) 277, 1515-1518.
3. Sims, K.D. & Robinson, M.B: Expression patterns and regulation of glutamate transporters in developing and adult nervous system. Crit Rev Neurobiol. (1999) 13, 169-197.
4. Choi, D.W., Maulucci-Gedde, M. & Kriegstein, A.R: Glutamate neurotoxicity in cortical cell culture. J Neurosci. (1987) 7, 357-368.
5. Cougnon, M., Planelles, G., Crowson, M.S., Shull, G.E., Rossier, B.C. & Jaisser, F: The rat distal colon p-ATPase alpha-subunit encodes a ouabain-sensitive H+, K+-ATPase. J Biol Chem. (1996) 271, 7277-7280.
6. Trotti, D., Danbolt, N.C. & Volterra, A: Glutamate transporters are oxidant-vulnerable: A molecular link between oxidative and excitotoxic neurodegeneration. Trends Pharmacol Sci. (1998) 19, 328-334.
7. Levenson, J., Weeber, E., Selcher, J.C., Kategaya, L.S., Sweatt, J.D. & Eskin, A: Long-term potentiation and contextual fear conditioning increase neuronal glutamate uptake. Nat Neurosci. (2002) 5, 155-161.
8. Rothstein, J.D., Martin, L., Levey, A.I., Dykes-Hoberg, M., Jin, L., Wu, D., Nash, N. & Kuncl, R.W: Localization of neuronal and glial glutamate transporters. Neuron (1994) 13, 713-725.
9. He, Y., Janssen, W.G., Rothstein, J.D. & Morrison, J.H: Differential synaptic localization of the glutamate transporter EAAC1 and glutamate receptor subunit GluR2 in the rat hippocampus. J Comp Neurol. (2000) 418, 255-269.
10. Zerangue, N. & Kavanaugh, M.P: Flux coupling in a neuronal glutamate transporter. Nature (1996) 383, 634-637.
11. Wadiche, J.I., Amara, S.G. & Kavanaugh, M.P: Ion fluxes associated with excitatory amino acid transport. Neuron (1995) 15, 721 –728.
12. Slotboom, D.J., Konings, W.N. & Lolkema, J.S: The structure of glutamate transporters shows channel-like features. FEBS Lett. (2001) 492, 183-186.
13. Robbins, T.W. & Everitt, B.J: Drug addiction: bad habits add up. Nature (1999) 398, 567-570.
14. Mansouri, F.A., Motamedi, F., Fathollahi, Y., Atapour, N. & Semnanian, S: Augmentation of LTP induced by primed-bursts tetanic stimulation in hippocampal CA1 area of morphine dependent rats. Brain Res. (1997) 769, 119-124.
15. Mansouri, F.A., Motamedi, F. & Fathollahi, Y: Chronic in vivo morphine administration facilitates primed-bursts-induced long-term potentiation of Schaffer collateral-CA1 synapses in hippocampal slices in vitro. Brain Res. (1999) 815, 419 –423.
16. Pu, L., Bao, G.B., Xu, N.J., Ma, L. & Pei, G: Hippocampal long-term potentiation is reduced by chronic morphine treatment and can be restored by re-exposure to opiates. J Neurosci. (2002) 22, 1914-1921.
17. Dingledine, R., Valentino, R.J., Bostock, E., King, M.E. & Chang, K.J: Down-regulation of delta but not mu opioid receptors in the hippocampal slice associated with loss of physiological response. Life Sci. (1983) 33 (Suppl.1), 333-336.
18. Vlaskovska, M., Schramm, M., Nylander, I., Kasakow, L., You, Z.B., Herrera-Marschitz, M. & Terenius, L: Opioid effects on 45Ca2+ uptake and glutamate release in rat cerebral cortex in primary culture. J Neurochem. (1997) 68, 517-524.
19. Tanaka, E., & North, R.A: Opioid actions on rat anterior cingulate cortex neurons in vitro. J Neursci. (1994) 14, 1106-1113.
20. Vorel, S.R., Liu, X., Haye, R.J., Spector, J.A.& Gardner, E.L:Relapse to cocaine-seeking after hippocampal theta burst stimulation. Science (2001) 292, 1175-1178.
21. Clark, J.A. & Amara, S.G: Amino-acid neurotransmitter transporters -structure, function, and molecular diversity. Bioessays (1993) 15, 323-332.
22. Beckman, M.L. & Quick, M.W: Neurotransmitter transporters: regulators of function and functional regulation. J Membrane Biol. (1998) 164, 1-10.
23. Xu, N.J., Bao, L., Fan, H.P., Bao, G.B., Pu, L., Lu, Y.J., Wu, C.F., Zhang, X. & Pei, G: Morphine Withdrawal Increases Glutamate Uptake and Surface Expression of Glutamate Transporter GLT1 at Hippocampal Synapses. J Neurosci. (2003) 23 (11), 4775– 4784.
24. Mao, J., Sung, B., Ji, R.R. & Lim, G: Chronic morphine induces downregulation of spinal glutamate transporters: implications in morphine tolerance and abnormal pain sensitivity. J Neurosci. (2002) 22, 8312-8323.
25. Vasilets, L.A: Diversity of regulatory phosphorylation of the Na+/K+-ATPase from mammalian kidneys and Xenopus oocytes by protein kinases. Characterisation of the phosphorylation site for PKC. Cell Physiol Biochem. (1997) 7, 1-18.
26. Zhu, Y.N., Fei, J. & Schwarz, W: Expression and transport function of the glutamate transporter EAAC1 in Xenopus oocytes is regulated by syntaxin 1A. J Neurosci Res. (2005) 79 (4), 503-508.
27. Schmalzing, G., Omay, H., Kr?ner, S., Gloor, S., Appelhans, H. & Schwarz, W: Up-regulation of sodium pump activity in Xenopus laevis oocytes by expression of heterologous ?1 subunits of the sodium pump. Biochem J. (1991) 279, 329-336.
28. Solis-Garrido, L.M., Pintado, A.J., Anderes-Mateos, E., Figueron, M., Matute, C. & Montiel, C: Cross-talk between native plasmalemmal Na+/Ca2+ exchanger and inositol 1,4,5-trisphosphate-sensitive Ca2+ internal store in xenopus oocyte J Biol Chem. (2004) 279, 52414-52424.
29. Michael, M.W. & Maria, A: Niflumic and flufenamic acids are potent reversible blockers of Ca2+-Activated Cl-channels in Xenopus oocytes. Mol Pharmacol. (1990) 37, 720-724.
30. Chen, J.G., Liu-Chen, S. & Rudnick, G.: External cysteine residues in the serotonin transporter. Biochemistry (1997) 36, 1479-1486.
31. Grabb, M.C. & Choi, D.W: Ischemic tolerance in murine cortical cell culture: Criticial role for NMDA receptors. J Neurosci. (1999) 19: 1657-1662.
32. Khodorov, B.I: Glutamate-induced deregulation of calcium homeostasis and mitochondrial dysfunction in mammalian central neurones. Prog Biophys Molec Biol. (2004) 86, 279-351.
33. Kanai, Y. & Hediger, M.A: The glutamate and neutral amino acid transporter family: physiological and pharmacological implications. Eur J Pharmacol. (2003) 479, 237-247.
34. Dowd, L.A., Coyle, A.J., Rothstein, J.D., Pritchett, D.B. & Robinson, M.B: Comparison of Na+-dependent glutamate transport activity in synaptosomes, C6 glioma, and xenopus oocytes expressing excitatory amino-acid carrier-1 (EAAC1). Mol Pharmacol. (1996) 49, 465-473.
35. Davis, K.E., Straff, D.J., Weinstein, E.A., Bannermann, P.G., Correale, D.M., Rothstein, J.D. & Robinson, M.B: Multiple signaling pathways regulate cell surface expression and activity of the excitatory amino acid carrier 1 subtype of Glutamate transporter in C6 glioma. J Neurosci. (1998) 18, 2475-2485.
36. Trotti, D., Peng, J.B., Dunlop, J. & Hediger, M.A: Inhibition of the glutamate transporter EAAC1 expressed in Xenopus oocytes by phorbol esters. Brain Res. (2001) 914, 196-203.
37. Gonzalez, M.I., Bannermann, P.G. & Robinson, M.B: Phorbol myristate acetate-dependent interaction of protein kinase Calpha and the neuronal glutamate transporter EAAC1. J Neurosci. (2003) 23, 5589-5593.
38. Lin, C.L.G., Orlov, I., Ruggerio, A.M., Dykes-Hoberg, M., Lee, A., Jack-son, M. & Rothstein, J.D: Modulation of the neuronal glutamate transporter EAAC1 by an interacting protein GTRAP3–18. Nature (2001) 410, 84–88.
39. Rothstein, J.D., Dykes-Hoberg, M., Pardo, C.A., Baristol, L.A., Jin, L., Kuncl, R.W., Kanai, Y., Hediger, M.A., Wang, Y., Schielke, J.P. & Welty, D.F: Knockout of glutamate transporters reveals a major role for astroglial transport in excitoxicity and clearence of ghitamate. neuron (1996) 18 (3), 675-686.
40. Zhang, G., Raol, Y.S., Hsu, F.C. & Brooks-Kayal, A.R: Long-term alterations in glutamate receptor and transporter expression following early-life seizures are associated with increased seizure susceptibility. J Neurochem (2004) 88, 91-101.
41. Nakagawa, T., Ozawa, T., Shige, K., Yamamoto, R., Minami, M., Satoh, M: Inhibition of morphine tolerance and dependence by MS-153, a glutamate transporter activator. Eur J Pharmacol. (2001) 419 (1), 39-45.
42. Cheng, P.Y., Svingos, A.L., Wang, H., Clarke, C.L., Jenab, S., Beczkowska, I.W., Inturrisi, C.E. &Pickel, V.M: Ultrastructural immunolabeling shows prominent presynaptic vesicular localization of delta-opioid receptor within both enkephalin-and nonenkephalin-containing axon terminals in the superficial layers of the rat cervical spinal cord. J Neurosci. (1995) 15, 5976-5988.
43. Commons, K.G. & Milner, T.A: Localization of delta opioid receptor immunoreactivity in interneurons and pyramidal cells in the rat hippocampus. J Comp Neurol. (1997) 381, 373-387.
44. Tao, F., Liaw, W.J., Zhang, B., Yaster, M., Rothstein, J.D. & Tao, Y.X: Evidence of neuronal excitatory amino acid carrier 1 expression in rat dorsal root ganglion neurons and their central terminals. Neuroscience (2004) 123, 1045-1051.
45. Guo, M., Xu, N.J., Li, Y.T., Yang, J.Y., Wu, C.F. & Pei, G: Morphine modulates glutamate release in the hippocampal CA1 area in mice. Neurosci Lett. (2005) 381, 12-15.
46. Chen, Y., Mestek, A., Liu, J., Yu, L: Molecular cloning of a rat kappa opioid receptor reveals sequence similarities to the mu and delta opioid receptors. Biochem J. (1993) 295, 625-628.
47. Finn, A.K. & Whistler, J.L: Endocytosis of the mu opioid receptor reduces tolerance and a cellular hallmark of opiate withdrawal. Neuron (2001) 32, 829-839.
48. Whistler, J.L., Enquist, J., Marley, A., Fong, J., Gladher, F., Tsuruda, P., Murray, S.R. & Von Zastrow, M: Modulation of postendocytic sorting of G protein-coupled receptors. Science (2002) 297, 615-620.
49. Waldhoer, M., Bartlett, S.E. & Whistler, J.L: Opioid receptors. Annu Rev Biochem. (2004) 27, 953-990.
50. Bao, L., Jin, S.X., Zhang ,C., Wang, L.H., Xu, Z.Z., Zhang, F.X., Wang, L.C., Ning, F.S., Cai, H.J., Guan ,J.S., Xiao, H.S., Xu, Z.Q., He, C., Hokfelt, T., Zhou, Z. & Zhang, X: Activation of delta opioid receptors induces receptor insertion and neuropeptide secretion. Neuron (2003) 37(1), 121-133.
51. Sora, I., Funada, M. & Uhl, G.R: The mu-opioid receptor is necessary for [D-Pen2,D-Pen5]enkephalin-induced analgesia. Eur J Pharmacol. (1997) 324, R1-2.
52. Zhang, J., Gibney, G.T., Zhao, P. & Xia, Y: Neuroprotective role of d-opioid receptors in cortical neurons. Am J Physiol Cell Physiol. (2002) 282, 1225-1234.