P2Y4受体在中枢神经系统的表达
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摘要
在分子、细胞、系统水平的研究证实细胞外ATP通过作用于嘌呤能受体作为重要的信号分子参与众多的生理和病理过程。P2Y受体是G蛋白藕联受体，哺乳动物有8种亚型(P2Y1,2,4,6,11,12,13,14)，P2Y_4受体在神经系统广泛表达，参与各种生理和病理功能，目前的研究主要集中在P2Y1受体，关于P2Y_4受体的研究比较少。本研究拟系统研究P2Y_4受体在大鼠中枢神经系统中的表达和分布特点，为深入研究其功能做基础。
本研究主要采用免疫组织化学染色和原位杂交等技术研究P2Y_4受体蛋白和mRNA在大鼠中枢神经系统的表达和分布特点。抗原吸附试验后再进行免疫染色，则无阳性结果；通过蛋白印迹实验检测大鼠大脑皮层提取物发现，在43kDa（约为P2Y_4受体分子量大小）处呈现单一条带，而抗血清吸附对照组中则检测不到该条带，说明我们所使用的P2Y_4受体的多克隆抗体具有较高的特异性。我们使用大鼠cDNA片段（337–350）转录合成的地高辛标记的反义探针进行原位杂交实验，得到阳性结果，使用地高辛标记的正义cRNA进行原位杂交，在相应区域则检测不到阳性信号。这些实验说明我们所使用的探针也具有较高的特异性。
我们的实验结果显示P2Y_4受体广泛分布于中枢神经系统中，且免疫组织化学染色结果和原位杂交结果具有高度一致性。
在主嗅球、嗅前核、初级嗅皮层区域、均有P2Y_4受体阳性染色，在这些区域的免疫染色主要集中在树突和细胞胞体，证实突触后膜ATP门控通道参与中枢嗅觉系统的快速兴奋性嘌呤传递途径。
P2Y_4受体强阳性染色集中在大脑皮层初级运动皮层，梨状皮层，嗅皮层、无颗粒岛叶皮层，提示P2Y_4受体可能参与神经局部环路的构建。
在海马中，在CA3区锥体细胞的轴突和CA1区的锥体细胞形成突触的区域呈现P2Y_4受体强的阳性染色，提示该受体可能参与海马的兴奋性神经递质传递或调节Schaeffer侧枝、苔藓纤维和perforant通路。
P2Y_4受体广泛分布在后脑比其它脑区呈现更强的阳性信号。P2Y_4受体强阳性染色分布在脑桥核、三叉神经中脑核、三叉神经运动核、疑核、下橄榄核、舌下神经核、迷走神经背核。
在小脑皮层中，蒲肯野细胞上P2Y_4受体阳性染色最强，且所有的蒲肯野细胞均为阳性染色。致密染色集中在细胞胞体和树突上，树突中存在P2Y_4受体同胞外ATP作为快速兴奋性递质的作用相吻合。
脊髓颈部、胸部、腰部、骶部灰质区均呈P2Y_4受体阳性染色。
我们的研究发现P2Y_4受体可以与VP（加压素）、OT（催产素）、Orexin(食欲素)共存，这些数据显示嘌呤和嘧啶可能通过P2Y_4受体调节神经肽催产素、加压素和食欲素的释放。P2Y_4受体和NR1受体共存，表明P2Y_4受体可能和NR1受体藕联调节神经元的生理和病理功能。
本课题联合使用免疫组织化学和原位杂交技术首次系统研究了P2Y_4受体蛋白和mRNA在小鼠中枢神经系统中的表达和分布特点，发现该受体广泛分布于中枢神经系统的神经元中。提示细胞外ATP可能也通过激活P2Y_4受体参与多种神经活动。
P2Y receptors are G protein-coupled receptors composed of eight known subunits(P2Y_(1,2,4,6,11,12,13,14)), which are involved in different functions in neural tissue. Thepresent study investigates the expression pattern of P2Y_4receptors in the rat centralnervous system
The specificity of the immunostaining has been verified by preabsorption, Westernblot, and combined use of immunohistochemistry and in situ hybridization. Neuronsexpressing P2Y_4receptors were distributed widely in the rat CNS. Heavy P2Y_4receptorimmunostaining was observed in the magnocellular neuroendocrine neurons of thehypothalamus, red nucleus, pontine nuclei, mesence-phalic trigeminal nucleus, motortrigeminal nucleus, ambiguous nucleus, inferior olive, hypoglossal nucleus, and dorsalmotor vagus nucleus. Both neurons and astrocytes express P2Y_4receptors. P2Y_4receptorimmunostaining signals were mainly confined to cell bodies and dendrites of neurons,suggesting that P2Y_4receptors are mainly involved in regulating postsynaptic events. Inthe hypothalamus, all the vasopressin (VP) and oxytocin (OT) neurons and all the orexinA neurons were immunoreactive for P2Y_4receptors. All the neurons expressing P2Y_4receptors were found to express N-methyl-D-aspartate receptor1(NR1). These datasuggest that purines and pyrimidines might be involved in regulation of the release of theneuropeptides VP, OT, and orexin in the rat hypothalamus via P2Y_4receptors. Further,the physiological and pathophysiological functions of the neurons may operate throughcoupling between P2Y_4receptors and NR1.
本研究主要采用免疫组织化学染色和原位杂交等技术研究P2Y_4受体蛋白和mRNA在大鼠中枢神经系统的表达和分布特点。抗原吸附试验后再进行免疫染色，则无阳性结果；通过蛋白印迹实验检测大鼠大脑皮层提取物发现，在43kDa（约为P2Y_4受体分子量大小）处呈现单一条带，而抗血清吸附对照组中则检测不到该条带，说明我们所使用的P2Y_4受体的多克隆抗体具有较高的特异性。我们使用大鼠cDNA片段（337–350）转录合成的地高辛标记的反义探针进行原位杂交实验，得到阳性结果，使用地高辛标记的正义cRNA进行原位杂交，在相应区域则检测不到阳性信号。这些实验说明我们所使用的探针也具有较高的特异性。
我们的实验结果显示P2Y_4受体广泛分布于中枢神经系统中，且免疫组织化学染色结果和原位杂交结果具有高度一致性。
在主嗅球、嗅前核、初级嗅皮层区域、均有P2Y_4受体阳性染色，在这些区域的免疫染色主要集中在树突和细胞胞体，证实突触后膜ATP门控通道参与中枢嗅觉系统的快速兴奋性嘌呤传递途径。
P2Y_4受体强阳性染色集中在大脑皮层初级运动皮层，梨状皮层，嗅皮层、无颗粒岛叶皮层，提示P2Y_4受体可能参与神经局部环路的构建。
在海马中，在CA3区锥体细胞的轴突和CA1区的锥体细胞形成突触的区域呈现P2Y_4受体强的阳性染色，提示该受体可能参与海马的兴奋性神经递质传递或调节Schaeffer侧枝、苔藓纤维和perforant通路。
P2Y_4受体广泛分布在后脑比其它脑区呈现更强的阳性信号。P2Y_4受体强阳性染色分布在脑桥核、三叉神经中脑核、三叉神经运动核、疑核、下橄榄核、舌下神经核、迷走神经背核。
在小脑皮层中，蒲肯野细胞上P2Y_4受体阳性染色最强，且所有的蒲肯野细胞均为阳性染色。致密染色集中在细胞胞体和树突上，树突中存在P2Y_4受体同胞外ATP作为快速兴奋性递质的作用相吻合。
脊髓颈部、胸部、腰部、骶部灰质区均呈P2Y_4受体阳性染色。
我们的研究发现P2Y_4受体可以与VP（加压素）、OT（催产素）、Orexin(食欲素)共存，这些数据显示嘌呤和嘧啶可能通过P2Y_4受体调节神经肽催产素、加压素和食欲素的释放。P2Y_4受体和NR1受体共存，表明P2Y_4受体可能和NR1受体藕联调节神经元的生理和病理功能。
本课题联合使用免疫组织化学和原位杂交技术首次系统研究了P2Y_4受体蛋白和mRNA在小鼠中枢神经系统中的表达和分布特点，发现该受体广泛分布于中枢神经系统的神经元中。提示细胞外ATP可能也通过激活P2Y_4受体参与多种神经活动。
P2Y receptors are G protein-coupled receptors composed of eight known subunits(P2Y_(1,2,4,6,11,12,13,14)), which are involved in different functions in neural tissue. Thepresent study investigates the expression pattern of P2Y_4receptors in the rat centralnervous system
The specificity of the immunostaining has been verified by preabsorption, Westernblot, and combined use of immunohistochemistry and in situ hybridization. Neuronsexpressing P2Y_4receptors were distributed widely in the rat CNS. Heavy P2Y_4receptorimmunostaining was observed in the magnocellular neuroendocrine neurons of thehypothalamus, red nucleus, pontine nuclei, mesence-phalic trigeminal nucleus, motortrigeminal nucleus, ambiguous nucleus, inferior olive, hypoglossal nucleus, and dorsalmotor vagus nucleus. Both neurons and astrocytes express P2Y_4receptors. P2Y_4receptorimmunostaining signals were mainly confined to cell bodies and dendrites of neurons,suggesting that P2Y_4receptors are mainly involved in regulating postsynaptic events. Inthe hypothalamus, all the vasopressin (VP) and oxytocin (OT) neurons and all the orexinA neurons were immunoreactive for P2Y_4receptors. All the neurons expressing P2Y_4receptors were found to express N-methyl-D-aspartate receptor1(NR1). These datasuggest that purines and pyrimidines might be involved in regulation of the release of theneuropeptides VP, OT, and orexin in the rat hypothalamus via P2Y_4receptors. Further,the physiological and pathophysiological functions of the neurons may operate throughcoupling between P2Y_4receptors and NR1.
引文
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[2] B.S. Khakh, R.A. North, P2X receptors as cell-surface ATP sensors in health and disease, Nature,2006,442(7102):527-532.
[3] M.P. Abbracchio, G. Burnstock, J.M. Boeynaems, E.A. Barnard, J.L. Boyer, C. Kennedy, G.E.Knight, M. Fumagalli, C. Gachet, K.A. Jacobson, G.A. Weisman, International Union ofPharmacology LVIII: update on the P2Y G protein-coupled nucleotide receptors: from molecularmechanisms and pathophysiology to therapy, Pharmacol Rev,2006,58(3):281-341.
[4] S. Hussl, S. Boehm, Functions of neuronal P2Y receptors, Pflugers Arch,2006,452(5):538-551.
[5] V. Ralevic, G. Burnstock, Receptors for purines and pyrimidines, Pharmacol Rev,1998,50(3):413-492.
[6] G. Burnstock, Physiology and pathophysiology of purinergic neurotransmission, Physiol Rev,2007,87(2):659-797.
[7] Y.D. Bogdanov, S.S. Wildman, M.P. Clements, B.F. King, G. Burnstock, Molecular cloning andcharacterization of rat P2Y4nucleotide receptor, Br J Pharmacol,1998,124(3):428-430.
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[1] G. Burnstock, Historical review: ATP as a neurotransmitter, Trends Pharmacol Sci,2006,27(3):166-176.
[2] B.S. Khakh, R.A. North, P2X receptors as cell-surface ATP sensors in health and disease, Nature,2006,442(7102):527-532.
[3] M.P. Abbracchio, G. Burnstock, J.M. Boeynaems, E.A. Barnard, J.L. Boyer, C. Kennedy, G.E.Knight, M. Fumagalli, C. Gachet, K.A. Jacobson, G.A. Weisman, International Union ofPharmacology LVIII: update on the P2Y G protein-coupled nucleotide receptors: from molecularmechanisms and pathophysiology to therapy, Pharmacol Rev,2006,58(3):281-341.
[4] S. Hussl, S. Boehm, Functions of neuronal P2Y receptors, Pflugers Arch,2006,452(5):538-551.
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[7] Y.D. Bogdanov, S.S. Wildman, M.P. Clements, B.F. King, G. Burnstock, Molecular cloning andcharacterization of rat P2Y4nucleotide receptor, Br J Pharmacol,1998,124(3):428-430.
[8] D. Moore, J. Chambers, H. Waldvogel, R. Faull, P. Emson, Regional and cellular distribution ofthe P2Y(1) purinergic receptor in the human brain: striking neuronal localisation, J Comp Neurol,2000,421(3):374-384.
[9] G. Hollopeter, H.M. Jantzen, D. Vincent, G. Li, L. England, V. Ramakrishnan, R.B. Yang, P.Nurden, A. Nurden, D. Julius, P.B. Conley, Identification of the platelet ADP receptor targetedby antithrombotic drugs, Nature,2001,409(6817):202-207.
[10] E.R. Lazarowski, L.G. Rochelle, W.K. O'Neal, C.M. Ribeiro, B.R. Grubb, V. Zhang, T.K.Harden, R.C. Boucher, Cloning and functional characterization of two murine uridine nucleotidereceptors reveal a potential target for correcting ion transport deficiency in cystic fibrosisgallbladder, J Pharmacol Exp Ther,2001,297(1):43-49.
[11] S. Amadio, N. D'Ambrosi, F. Cavaliere, B. Murra, G. Sancesario, G. Bernardi, G. Burnstock, C.Volonte, P2receptor modulation and cytotoxic function in cultured CNS neurons,Neuropharmacology,2002,42(4):489-501.
[12] C. Hervas, R. Perez-Sen, M.T. Miras-Portugal, Coexpression of functional P2X and P2Ynucleotide receptors in single cerebellar granule cells, J Neurosci Res,2003,73(3):384-399.
[13] M.P. Abbracchio, S. Ceruti, Roles of P2receptors in glial cells: focus on astrocytes, PurinergicSignal,2006,2(4):595-604.
[14] D. Communi, N.S. Gonzalez, M. Detheux, S. Brezillon, V. Lannoy, M. Parmentier, J.M.Boeynaems, Identification of a novel human ADP receptor coupled to G(i), J Biol Chem,2001,276(44):41479-41485.
[15] T. Nguyen, L. Erb, G.A. Weisman, A. Marchese, H.H. Heng, R.C. Garrad, S.R. George, J.T.Turner, B.F. O'Dowd, Cloning, expression, and chromosomal localization of the human uridinenucleotide receptor gene, J Biol Chem,1995,270(52):30845-30848.
[16] G. Collo, R.A. North, E. Kawashima, E. Merlo-Pich, S. Neidhart, A. Surprenant, G. Buell,Cloning OF P2X5and P2X6receptors and the distribution and properties of an extended familyof ATP-gated ion channels, J Neurosci,1996,16(8):2495-2507.
[17] T.E. Webb, D.J. Henderson, J.A. Roberts, E.A. Barnard, Molecular cloning and characterizationof the rat P2Y4receptor, J Neurochem,1998,71(4):1348-1357.
[18] N. Suarez-Huerta, V. Pouillon, J. Boeynaems, B. Robaye, Molecular cloning and characterizationof the mouse P2Y4nucleotide receptor, Eur J Pharmacol,2001,416(3):197-202.
[19] D.J. Moore, J.K. Chambers, J.P. Wahlin, K.B. Tan, G.B. Moore, O. Jenkins, P.C. Emson, P.R.Murdock, Expression pattern of human P2Y receptor subtypes: a quantitative reversetranscription-polymerase chain reaction study, Biochim Biophys Acta,2001,1521(1-3):107-119.
[20] N. Teramoto, L. Szekely, K. Pokrovskaja, L.F. Hu, T. Yoshino, T. Akagi, G. Klein, Simultaneousdetection of two independent antigens by double staining with two mouse monoclonal antibodies,J Virol Methods,1998,73(1):89-97.
[21] Z. Xiang, C. He, G. Burnstock, P2X5receptors are expressed on neurons containing argininevasopressin and nitric oxide synthase in the rat hypothalamus, Brain Res,2006,1099(1):56-63.
[22] Z. Xiang, L. Jiang, Z. Kang, Transient expression of somatostatin mRNA in developing ganglioncell layers of rat retina, Brain Res Dev Brain Res,2001,128(1):25-33.
[23] M. Simard, G. Arcuino, T. Takano, Q.S. Liu, M. Nedergaard, Signaling at the gliovascularinterface, J Neurosci,2003,23(27):9254-9262.
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