伤害性感受器NK-1受体的激活增强TRPV1和TTX不敏感钠通道活动的机制研究
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摘要
背根节介导伤害性信息的初级感觉神经元的外周终末,称为“伤害性感受器”或“痛觉感受器”。伤害性感受器将伤害性刺激换能,转变成神经冲动,传递到脊髓背角,经初步整合传递到大脑进行信息加工,最终产生痛觉。背根节中的伤害性感觉神经元作为痛觉传导的第一级神经元,在痛觉产生和维持中发挥重要的作用。
P物质(SP)是速激肽家族的主要成员,在神经系统广泛表达。在外周神经系统中,主要存在伤害性感觉神经元上,是外周伤害性传入信息向脊髓背角神经元传递的主要信使之一。SP在背根节神经元胞体合成,双向地输送到伤害性感觉神经元的中枢末梢和外周末梢,包含在大的致密的囊泡中。在中枢端的脊髓背角,SP阳性的神经末梢与背角Ⅰ层的投射神经元连接,传递伤害性信息;而在外周神经末梢,伤害性感受器的SP作为炎症因子之一,释放到外周,激活肥大细胞,产生外周敏化机制。速激肽家族有三种受体:NK-1、NK-2和NK-3,其中SP对NK-1的亲和力最高,因此,NK-1被公认为SP受体。
SP作为脊髓伤害性初级传入信使,在行为、细胞和分子水平已进行了深入的研究。如外周伤害性刺激引起SP在脊髓背角浅层释放;脊髓施加NK-1激动剂和拮抗剂,可分别增强和抑制脊髓背角痛敏神经元活动、伤害性反射和Fos表达;NK-1或者SP基因敲除的动物,急性痛不受影响,但是慢性痛的形成过程大大减慢。但是关于SP参与外周敏化的机制以及细胞内信号通路却知之甚少。本实验室以前的工作表明,含有SP的背根节神经元可能表达NK-1自身受体;SP引起外周的热痛觉过敏,而这一过程与表达NK-1的肥大细胞没有关系。本论文应用免疫组织化学、蛋白免疫印迹、全细胞膜片钳以及钙成像等多种技术,对NK-1自身受体的存在、NK-1对介导热痛敏的辣椒素受体TRPV1和TTX不敏感钠通道的调制,以及可能的作用机制进行了研究。
一.形态学观察
背根神经节细胞上存在NK-1受体。该受体合成后被运输到外周神经末梢,在完全福氏佐剂致炎2天之后,表达量明显升高。同时在DRG小细胞上存在一定比例NK-1与SP双标神经元和NK-1与TRPV1双标的神经元。
二.SP对TRPV1的调制
1.SP增强TRPV1活动
TRPV1受体是一个非选择性的阳离子通道,在全细胞膜片钳和钙成像试验中,TRPV1受体特异的激动剂辣椒素分别引起细胞的内向电流以及胞内钙离子浓度的瞬时升高,而SP均能够引起TRPV1反应的增强。75.8%的背根神经节小细胞(直径＜25μm)对辣椒素有反应。其中在49.6%的辣椒素反应阳性神经元中,SP对辣椒素反应有增强作用(409.12±44.54%)。NK-1受体的激动剂[Sar~9,Met(O_2)11]SP(Sar-SP,1μM)能够模拟SP的作用;NK-1特异性的拮抗剂GR82,334(1μM)和WIN58,078(5μM)能够特异性的抑制SP引起的反应,而NK-2和NK-3的拮抗剂L659,187(1μM)和SR-142,801(1μM)不影响SP引起的增强作用,提示SP特异的通过NK-1受体调节TRPV1受体的功能。
2.信号转导机制分析
G蛋白特异拮抗剂GDP-β-s(1mM,胞内)、PKC的抑制剂BIM(1μM)和Chel.C(1μM)以及PKCε亚型的特异拮抗剂εV_(1-2)(200μM,胞内)也特异性的抑制SP引起的反应,PKC的激活剂PMA(0.6μM)能够模拟SP引起辣椒素反应的增大;PKA的拮抗剂H89(1μM)以及细胞内钙的螯合剂BEPTA不能抑制SP引起的辣椒素反应的增强。以上结果提示SP在外周神经末梢激活G蛋白偶联的NK-1受体,激活PKC的亚型PKCε,从而磷酸化TRPV1受体,产生热痛觉过敏的作用。
三.SP调制TTX不敏感钠通道
TTX不敏感的钠通道包含两种亚型Nav1.8和Nav1.9,两者根据电流性质的不同,分别参与动作电位的产生和静息膜电位的维持。我们采用全细胞膜片钳的方法,使用不同的电压刺激方法,成功分离了两种亚型钠离子通道的电流。
1.Nav1.8
在78.3%(22/28)的背根神经节小细胞上能够记录到Nav1.8介导的高阈值激活的钠电流,其中在40.9%(9/22)的Nav1.8阳性反应细胞中,特异性NK-1的激动剂Sar—SP(1μM)显著性的增强Nav1.8亚型钠通道介导的电流(123.52±2.83%);且Sar—SP使Nav1.8亚型钠通道的激活和稳态失活曲线向超极化方向移动。
2.Nav1.9
在62.6%(20/32)背根神经节小细胞上能够记录到低阈值激活的不失活的Nav1.9介导的钠电流,在35%(7/20)的Nav1.9阳性反应细胞上,Sar—SP显著性的增强Nav1.9亚型钠通道介导的电流(110.27±2.33%)。提示SP通过增强两种亚型钠离子通道的敏感性提高伤害性感受器的兴奋性。
综上所述,本论文首次系统的论述了SP通过激活伤害性感受器上的NK-1自身受体,激活细胞内的信号通路,增强伤害性感受器上TRPV1受体和TTX不敏感钠通道的敏感性,从而产生外周敏化的机制。这项研究不仅揭示了新的外周敏化的机制,也为我们进一步了解炎症过程中的痛觉过敏的产生和维持机制提供了重要的启示。
Chemical (capsaicin and acid) or physical (heat) variety can excite nociceptors, enabling the cell to generate action potentials which propagate to the dorsal horn of spinal cord after primary integration. The primary afferent nociceptive neurons as the first order neurons play a key role in nociception.
Substance P (SP), which mainly exists in a subtype of small Dorsal root ganglion (DRG) neurons, is a kind of mammalian tachykinin. After synthesis, it is packed into the dense vesicles and transferred to the central and peripheral terminals. At the central terminals, the SP positive nerves terminate in the lamina I of spinal horn, and pass the nociceptive information to the spinal neurons. At the peripheral, SP is released as an inflammatory modulator, sensitizing the nociceptive perception. There are three kinds of tachykinin receptors, NK-1, NK-2 and NK-3, SP has the highest affinity to NK-1. When activated, it subsequently stimulates PLC-catalysed hydrolysis of PtdIns(4,5)P_2, consequently releasing Ca~(2+) from intracellular stores and activating protein kinase C (PKC).
In peripheral, abundant NK-1 receptors existed in mast cells but whether the NK-1 autoreceptors in nociceptors existing remains controversy. Our previous work revealed that SP induced the thermal hyperalgesia without the activation of mast cells, which indicated a direct effect of SP on nociceptors.
Using immunohistochemistry, western blot, whole cell patch clamp, calcium imaging and pain behavioral test, we for the first time characterized the NK-1 autoreceptors in primary sensory neurons.
1. The existence of NK-1 in DRG
Evidence of immunohistochemistry and western blot revealed a wide distribution of NK-1 receptors in primary sensory neurons and co-existent with SP and TRPV1, which significant up-regulated after CFA-induced inflammation. There are two key channels in thermal transduction and propagation, TRPV1 and the TTX-resistant sodium channels, which indicates that SP sensitizes nociceptors through the interaction of NK-1 with TRPV1 receptors and the TTX-resistant sodium channels.
2. The "crosstalk" between NK-1 and TRPV1
a) SP potentiates TRPV1 responses
SP potentiated TRPV1 responses through NK1 receptors. TRPV1 is a non-selective cation channel, which is activated by capsaicin or noxious heat stimuli. By the methods of whole cell patch clamp and calcium imaging, an inward non-selective cationic current and a transient increment of intracellular calcium concentration were elicited by capsaicin. 75.8% of recording neurons responded to capsaicin, in which, 49.6% responded to SP (1μM). The mean potentiation of TRPV1 responses were 409.12±44.54% of control. The effect of SP was mimicked by a selective NK-1 agonist [Sar~9, Met(O_2)11]SP (Sar-SP, 1μM) and blocked by the specific NK-1 antagonists, WIN51,708 (5μM) and GR82,334 (1μM), while the NK-2 and NK-3 antagonists, L659, 187 (1μM) and SR-142, 801 (1μM) failed to block the effect of SP.
b) Cellular mechanism of NK-1
The effect of Sar-SP was also abolished by the antagonist of G protein, GDP-β-s (1 mM intracellular), the inhibitors of PKC, BIM (1μM) and Chel.C (5μM) and the PKCs specific inhibitor,εV1-2 (200μM, intracellular), but not the PKA inhibitor, H89 (1μM), pre-treatment with Phorbol 12-myristate 13-acetate (PMA, 0.6μM), the activator of PKC, prevented the further enhancement of TRPV1 response, all these results suggested a new signaling pathway from NK-1 to TRPV1 through PKCεphosphorylation.
3. SP potentiates TTX-resistant sodium channels sensitivity
There are two TTX-resistant sodium channels subtypes, Nav1.8 and Nav1.9, specifically expressed in small DRG neurons, with distinct characters of activation and inactivation. By method of whole cell patch clamp, we successfully separated two kinds of TTX-resistant sodium currents, supposed to be induced by Nav1.8 and Nav1.9 seperatelly. Sar-SP potentiated both the Nav1.8 and Nav1.9 currents.
a) Nav1.8
Of 22 DRG neurons with Nav1.8 currents, 9 responded to Sar-SP (1μM), with a rapid increase in the peak of Nav1.8 currents (123.52±2.83%) and a hyperpolarizing shift of both the active and steady-state inactive curve.
b) Nav1.9
Of 20 DRG neurons with Nav1.9 currents, 7 responded to Sar-SP (1μM) with also an increase in Nav1.9 currents (110.27±2.33%), suggesting a role of Sar-SP on enhancement of cellular excitability.
The present work not only supports the expression of NK-1 autoreceptors in nociceptors, but also strongly indicates a novel positive feedback signaling pathway through NK- 1 autoreceptor in processing peripheral nociceptive information.
P物质(SP)是速激肽家族的主要成员,在神经系统广泛表达。在外周神经系统中,主要存在伤害性感觉神经元上,是外周伤害性传入信息向脊髓背角神经元传递的主要信使之一。SP在背根节神经元胞体合成,双向地输送到伤害性感觉神经元的中枢末梢和外周末梢,包含在大的致密的囊泡中。在中枢端的脊髓背角,SP阳性的神经末梢与背角Ⅰ层的投射神经元连接,传递伤害性信息;而在外周神经末梢,伤害性感受器的SP作为炎症因子之一,释放到外周,激活肥大细胞,产生外周敏化机制。速激肽家族有三种受体:NK-1、NK-2和NK-3,其中SP对NK-1的亲和力最高,因此,NK-1被公认为SP受体。
SP作为脊髓伤害性初级传入信使,在行为、细胞和分子水平已进行了深入的研究。如外周伤害性刺激引起SP在脊髓背角浅层释放;脊髓施加NK-1激动剂和拮抗剂,可分别增强和抑制脊髓背角痛敏神经元活动、伤害性反射和Fos表达;NK-1或者SP基因敲除的动物,急性痛不受影响,但是慢性痛的形成过程大大减慢。但是关于SP参与外周敏化的机制以及细胞内信号通路却知之甚少。本实验室以前的工作表明,含有SP的背根节神经元可能表达NK-1自身受体;SP引起外周的热痛觉过敏,而这一过程与表达NK-1的肥大细胞没有关系。本论文应用免疫组织化学、蛋白免疫印迹、全细胞膜片钳以及钙成像等多种技术,对NK-1自身受体的存在、NK-1对介导热痛敏的辣椒素受体TRPV1和TTX不敏感钠通道的调制,以及可能的作用机制进行了研究。
一.形态学观察
背根神经节细胞上存在NK-1受体。该受体合成后被运输到外周神经末梢,在完全福氏佐剂致炎2天之后,表达量明显升高。同时在DRG小细胞上存在一定比例NK-1与SP双标神经元和NK-1与TRPV1双标的神经元。
二.SP对TRPV1的调制
1.SP增强TRPV1活动
TRPV1受体是一个非选择性的阳离子通道,在全细胞膜片钳和钙成像试验中,TRPV1受体特异的激动剂辣椒素分别引起细胞的内向电流以及胞内钙离子浓度的瞬时升高,而SP均能够引起TRPV1反应的增强。75.8%的背根神经节小细胞(直径＜25μm)对辣椒素有反应。其中在49.6%的辣椒素反应阳性神经元中,SP对辣椒素反应有增强作用(409.12±44.54%)。NK-1受体的激动剂[Sar~9,Met(O_2)11]SP(Sar-SP,1μM)能够模拟SP的作用;NK-1特异性的拮抗剂GR82,334(1μM)和WIN58,078(5μM)能够特异性的抑制SP引起的反应,而NK-2和NK-3的拮抗剂L659,187(1μM)和SR-142,801(1μM)不影响SP引起的增强作用,提示SP特异的通过NK-1受体调节TRPV1受体的功能。
2.信号转导机制分析
G蛋白特异拮抗剂GDP-β-s(1mM,胞内)、PKC的抑制剂BIM(1μM)和Chel.C(1μM)以及PKCε亚型的特异拮抗剂εV_(1-2)(200μM,胞内)也特异性的抑制SP引起的反应,PKC的激活剂PMA(0.6μM)能够模拟SP引起辣椒素反应的增大;PKA的拮抗剂H89(1μM)以及细胞内钙的螯合剂BEPTA不能抑制SP引起的辣椒素反应的增强。以上结果提示SP在外周神经末梢激活G蛋白偶联的NK-1受体,激活PKC的亚型PKCε,从而磷酸化TRPV1受体,产生热痛觉过敏的作用。
三.SP调制TTX不敏感钠通道
TTX不敏感的钠通道包含两种亚型Nav1.8和Nav1.9,两者根据电流性质的不同,分别参与动作电位的产生和静息膜电位的维持。我们采用全细胞膜片钳的方法,使用不同的电压刺激方法,成功分离了两种亚型钠离子通道的电流。
1.Nav1.8
在78.3%(22/28)的背根神经节小细胞上能够记录到Nav1.8介导的高阈值激活的钠电流,其中在40.9%(9/22)的Nav1.8阳性反应细胞中,特异性NK-1的激动剂Sar—SP(1μM)显著性的增强Nav1.8亚型钠通道介导的电流(123.52±2.83%);且Sar—SP使Nav1.8亚型钠通道的激活和稳态失活曲线向超极化方向移动。
2.Nav1.9
在62.6%(20/32)背根神经节小细胞上能够记录到低阈值激活的不失活的Nav1.9介导的钠电流,在35%(7/20)的Nav1.9阳性反应细胞上,Sar—SP显著性的增强Nav1.9亚型钠通道介导的电流(110.27±2.33%)。提示SP通过增强两种亚型钠离子通道的敏感性提高伤害性感受器的兴奋性。
综上所述,本论文首次系统的论述了SP通过激活伤害性感受器上的NK-1自身受体,激活细胞内的信号通路,增强伤害性感受器上TRPV1受体和TTX不敏感钠通道的敏感性,从而产生外周敏化的机制。这项研究不仅揭示了新的外周敏化的机制,也为我们进一步了解炎症过程中的痛觉过敏的产生和维持机制提供了重要的启示。
Chemical (capsaicin and acid) or physical (heat) variety can excite nociceptors, enabling the cell to generate action potentials which propagate to the dorsal horn of spinal cord after primary integration. The primary afferent nociceptive neurons as the first order neurons play a key role in nociception.
Substance P (SP), which mainly exists in a subtype of small Dorsal root ganglion (DRG) neurons, is a kind of mammalian tachykinin. After synthesis, it is packed into the dense vesicles and transferred to the central and peripheral terminals. At the central terminals, the SP positive nerves terminate in the lamina I of spinal horn, and pass the nociceptive information to the spinal neurons. At the peripheral, SP is released as an inflammatory modulator, sensitizing the nociceptive perception. There are three kinds of tachykinin receptors, NK-1, NK-2 and NK-3, SP has the highest affinity to NK-1. When activated, it subsequently stimulates PLC-catalysed hydrolysis of PtdIns(4,5)P_2, consequently releasing Ca~(2+) from intracellular stores and activating protein kinase C (PKC).
In peripheral, abundant NK-1 receptors existed in mast cells but whether the NK-1 autoreceptors in nociceptors existing remains controversy. Our previous work revealed that SP induced the thermal hyperalgesia without the activation of mast cells, which indicated a direct effect of SP on nociceptors.
Using immunohistochemistry, western blot, whole cell patch clamp, calcium imaging and pain behavioral test, we for the first time characterized the NK-1 autoreceptors in primary sensory neurons.
1. The existence of NK-1 in DRG
Evidence of immunohistochemistry and western blot revealed a wide distribution of NK-1 receptors in primary sensory neurons and co-existent with SP and TRPV1, which significant up-regulated after CFA-induced inflammation. There are two key channels in thermal transduction and propagation, TRPV1 and the TTX-resistant sodium channels, which indicates that SP sensitizes nociceptors through the interaction of NK-1 with TRPV1 receptors and the TTX-resistant sodium channels.
2. The "crosstalk" between NK-1 and TRPV1
a) SP potentiates TRPV1 responses
SP potentiated TRPV1 responses through NK1 receptors. TRPV1 is a non-selective cation channel, which is activated by capsaicin or noxious heat stimuli. By the methods of whole cell patch clamp and calcium imaging, an inward non-selective cationic current and a transient increment of intracellular calcium concentration were elicited by capsaicin. 75.8% of recording neurons responded to capsaicin, in which, 49.6% responded to SP (1μM). The mean potentiation of TRPV1 responses were 409.12±44.54% of control. The effect of SP was mimicked by a selective NK-1 agonist [Sar~9, Met(O_2)11]SP (Sar-SP, 1μM) and blocked by the specific NK-1 antagonists, WIN51,708 (5μM) and GR82,334 (1μM), while the NK-2 and NK-3 antagonists, L659, 187 (1μM) and SR-142, 801 (1μM) failed to block the effect of SP.
b) Cellular mechanism of NK-1
The effect of Sar-SP was also abolished by the antagonist of G protein, GDP-β-s (1 mM intracellular), the inhibitors of PKC, BIM (1μM) and Chel.C (5μM) and the PKCs specific inhibitor,εV1-2 (200μM, intracellular), but not the PKA inhibitor, H89 (1μM), pre-treatment with Phorbol 12-myristate 13-acetate (PMA, 0.6μM), the activator of PKC, prevented the further enhancement of TRPV1 response, all these results suggested a new signaling pathway from NK-1 to TRPV1 through PKCεphosphorylation.
3. SP potentiates TTX-resistant sodium channels sensitivity
There are two TTX-resistant sodium channels subtypes, Nav1.8 and Nav1.9, specifically expressed in small DRG neurons, with distinct characters of activation and inactivation. By method of whole cell patch clamp, we successfully separated two kinds of TTX-resistant sodium currents, supposed to be induced by Nav1.8 and Nav1.9 seperatelly. Sar-SP potentiated both the Nav1.8 and Nav1.9 currents.
a) Nav1.8
Of 22 DRG neurons with Nav1.8 currents, 9 responded to Sar-SP (1μM), with a rapid increase in the peak of Nav1.8 currents (123.52±2.83%) and a hyperpolarizing shift of both the active and steady-state inactive curve.
b) Nav1.9
Of 20 DRG neurons with Nav1.9 currents, 7 responded to Sar-SP (1μM) with also an increase in Nav1.9 currents (110.27±2.33%), suggesting a role of Sar-SP on enhancement of cellular excitability.
The present work not only supports the expression of NK-1 autoreceptors in nociceptors, but also strongly indicates a novel positive feedback signaling pathway through NK- 1 autoreceptor in processing peripheral nociceptive information.
引文
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