锌指蛋白ZBTB20通过调节伤害感受神经元TRP通道调控伤害感受和痛觉
发布时间：2018-07-15 12:16
【摘要】：疼痛的调控机制一直是神经生物学的研究热点。在哺乳动物中,背根神经节(dorsal root ganglion, DRG)的小神经元是感受和传导疼痛信号的伤害感受神经元。伤害感受小神经元又可进一步分成肽能和非肽能两个不同的亚群。肽能小神经元可分泌神经肽、P物质、降钙素基因相关肽(calcitonin-gene related peptide, CGRP),表达神经生长因子受体TrkA。非肽能小神经元表达神经营养因子受体c-Ret,受胶质细胞源性神经营养因子(glial-derived neurotrophic factor, GDNF)等的调节,表达G蛋白偶联受体家族Mrgpr和嘌呤受体P2X3,植物凝集素(isolectin B4, IB4)标记阳性。痛觉感受是通过DRG中伤害感受神经元上的通道或受体感受伤害性刺激的,瞬时感受器电位(transient receptor potential,TRP)通道在其中起着重要的作用。TRP通道是温度感受相关的非选择性阳离子通道,激活时主要引起Ca2+内流,包括6个亚家族：TRPC、TRPV、TRPM、TRPML、TRPPP和TRPA。其中TRPV1是感受伤害性热刺激的内源性感受器,TRPA1与TRPM8则在感受伤害性冷刺激中发挥重要作用。但是这些通道的表达如何调节目前还知之甚少。许多转录因子在伤害感受神经元的发育过程中发挥了重要的调节作用。其中,神经发生素1(neurogenin 1,NGN1)是大部分伤害感受神经元发育所必需的。同源基因Brn3a和锌指蛋白klf7在伤害感受神经元存活及维持TrkA表达等方面具有重要的作用。Runxl(Runt domain transcription factor 1)可激活多种与痛觉相关的通道蛋白及受体,如TRPV1、TRPA1、μ型阿片样受体(μ opioid receptor, MOR)和嘌呤能受体P2X3等,并抑带CGRP和P物质的表达。此外,转录因子Tlx3能与Runxl共同协调调节一些伤害感受神经元及嘌呤受体的表达。然而,目前在调节伤害感受神经元TRP通道表达的转录因子研究方面还未见报道。锌指蛋白ZBTB20是导师章卫平所在课题组自主发现并率先报道的新型转录因子。ZBTB20由741个氨基酸残基组成,N端含有BTB/POZ结构域,C端含有5个C2H2锌指结构域,是BTB锌指蛋白亚家族成员之一。研究发现ZBTB20在中枢神经系统中高表达,并且在海马的分化发育及功能方面具有重要的作用,但是它对周围神经系统的作用还未见报道。在本研究中我们发现ZBTB20在DRG中伤害感受神经元高表达。通过建立外周伤害感受神经元特异性ZBTB20敲除(peripheral nociceptor-specific ZBTB20 knockout, PN-ZB20KO)小鼠模型并结合组织学、行为学、电生理及分子生物学等研究手段,我们发现PN-ZB20KO小鼠DRG中TRP通道家族TRPV1、TRPA1和TRPM8表达显著降低,而且这些通道激动剂诱发的钙内流以及通道电流下降。PN-ZB20KO小鼠对热刺激、机械刺激和免疫刺激引起的疼痛反应减弱。我们的研究表明ZBTB20通过调节伤害感受神经元TRP通道的表达调控伤害感受和痛觉。
[Abstract]:The mechanism of pain regulation has been a hot topic in neurobiology. In mammals, the small neurons of the dorsal root ganglion (dorsal root ganglion, DRG) are nociceptive neurons that sense and transmit pain signals. The nociceptive small neurons can be further divided into two subgroups of peptidergic and non-peptidergic. Small peptidergic neurons secrete neuropeptide substance P, calcitonin-gene related peptide, and express nerve growth factor receptor TrkA. Non-peptidergic small neurons expressed neurotrophic factor receptor c-Ret, which was regulated by glial-derived neurotrophic factor (GDNF), and expressed isolectin B4 (IB4) labeled isolectin B4 in the G protein-coupled receptor family Mrgpr, P2X3 and isolectin B4 (IB4). Pain perception is induced by nociceptive stimulation through nociceptive neurons or receptors in DRGs, in which transient receptor potential (transient receptor potentialtr) channels play an important role. TRP channels are non-selective cationic channels associated with temperature sensing. During activation, Ca2 + influx was mainly induced, including 6 subfamilies: TRPC, TRPV, TRPMML, TRPPP and TRPA. TRPV1 is the endogenous receptor of nociceptive heat stimulation, and TRPA1 and TRPM8 play an important role in nociceptive cold stimulation. But little is known about how these channels are regulated. Many transcription factors play an important role in the development of nociceptive neurons. Among them, neurogenin 1 NGN1 is necessary for the development of most nociceptive neurons. The homologous genes Brn3a and zinc finger protein klf7 play an important role in the survival of nociceptive neurons and the maintenance of TrkA expression. Runxl (Runt domain transcription factor 1) can activate many channel proteins and receptors associated with pain perception. For example, TRPV1 / TRPA1, 渭 opioid receptor (Mor) and purinergic receptor P2X3, etc., also inhibit the expression of CGRP and substance P. In addition, transcription factor Tlx3 can coordinate with Runxl to regulate the expression of some nociceptive neurons and purine receptors. However, transcriptional factors regulating the expression of TRP channels in nociceptive neurons have not been reported. Zinc finger protein ZBTB20 is a novel transcription factor. ZBTB20 consists of 741 amino acid residues. ZBTB20 contains five C2H2 zinc finger domains at the C-terminal of BTB / POZ domain. It is a member of BTB zinc finger protein subfamily. It has been found that ZBTB20 is highly expressed in the central nervous system and plays an important role in the differentiation and development of the hippocampus, but its effect on the peripheral nervous system has not been reported. In this study, we found that ZBTB 20 is highly expressed in DRG nociceptive neurons. The peripheral nociceptor-specific ZBTB20 knockout (PN-ZB20KO) mouse model was established and combined with histological, behavioral, electrophysiological and molecular biological methods. We found that the expression of TRPV1 / TRPA1 and TRPM8 in DRG of PN-ZB20KO mice was significantly decreased, and the calcium influx induced by these channel agonists and the decrease of channel current in PN-ZB20KO mice were decreased to the pain response induced by thermal, mechanical and immune stimulation. Our study shows that ZBTB20 regulates pain perception and pain perception by regulating the expression of TRP channels in nociceptive neurons.
【学位授予单位】：第二军医大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R402
本文编号：2124044
[Abstract]:The mechanism of pain regulation has been a hot topic in neurobiology. In mammals, the small neurons of the dorsal root ganglion (dorsal root ganglion, DRG) are nociceptive neurons that sense and transmit pain signals. The nociceptive small neurons can be further divided into two subgroups of peptidergic and non-peptidergic. Small peptidergic neurons secrete neuropeptide substance P, calcitonin-gene related peptide, and express nerve growth factor receptor TrkA. Non-peptidergic small neurons expressed neurotrophic factor receptor c-Ret, which was regulated by glial-derived neurotrophic factor (GDNF), and expressed isolectin B4 (IB4) labeled isolectin B4 in the G protein-coupled receptor family Mrgpr, P2X3 and isolectin B4 (IB4). Pain perception is induced by nociceptive stimulation through nociceptive neurons or receptors in DRGs, in which transient receptor potential (transient receptor potentialtr) channels play an important role. TRP channels are non-selective cationic channels associated with temperature sensing. During activation, Ca2 + influx was mainly induced, including 6 subfamilies: TRPC, TRPV, TRPMML, TRPPP and TRPA. TRPV1 is the endogenous receptor of nociceptive heat stimulation, and TRPA1 and TRPM8 play an important role in nociceptive cold stimulation. But little is known about how these channels are regulated. Many transcription factors play an important role in the development of nociceptive neurons. Among them, neurogenin 1 NGN1 is necessary for the development of most nociceptive neurons. The homologous genes Brn3a and zinc finger protein klf7 play an important role in the survival of nociceptive neurons and the maintenance of TrkA expression. Runxl (Runt domain transcription factor 1) can activate many channel proteins and receptors associated with pain perception. For example, TRPV1 / TRPA1, 渭 opioid receptor (Mor) and purinergic receptor P2X3, etc., also inhibit the expression of CGRP and substance P. In addition, transcription factor Tlx3 can coordinate with Runxl to regulate the expression of some nociceptive neurons and purine receptors. However, transcriptional factors regulating the expression of TRP channels in nociceptive neurons have not been reported. Zinc finger protein ZBTB20 is a novel transcription factor. ZBTB20 consists of 741 amino acid residues. ZBTB20 contains five C2H2 zinc finger domains at the C-terminal of BTB / POZ domain. It is a member of BTB zinc finger protein subfamily. It has been found that ZBTB20 is highly expressed in the central nervous system and plays an important role in the differentiation and development of the hippocampus, but its effect on the peripheral nervous system has not been reported. In this study, we found that ZBTB 20 is highly expressed in DRG nociceptive neurons. The peripheral nociceptor-specific ZBTB20 knockout (PN-ZB20KO) mouse model was established and combined with histological, behavioral, electrophysiological and molecular biological methods. We found that the expression of TRPV1 / TRPA1 and TRPM8 in DRG of PN-ZB20KO mice was significantly decreased, and the calcium influx induced by these channel agonists and the decrease of channel current in PN-ZB20KO mice were decreased to the pain response induced by thermal, mechanical and immune stimulation. Our study shows that ZBTB20 regulates pain perception and pain perception by regulating the expression of TRP channels in nociceptive neurons.
【学位授予单位】：第二军医大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R402
【共引文献】
相关博士学位论文 前2条
1 邹宇;CGRP和IB4（+）C纤维在神经病理性疼痛阳—阴性症状中的作用[D];中南大学;2013年
2 汪一;T型钙通道阻滞剂强化加巴喷丁治疗糖尿病神经病理性疼痛的效果及可能的机制[D];北京协和医学院;2014年
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