Endothelin potentiates TRPV1 via ETA receptor-mediated activation of protein kinase C.
Endothelin potentiates TRPV1 via ETA receptor-mediated activation of protein kinase C.
复制标题
DOI：
10.1186/1744-8069-3-35
复制
发表时间：
2007-11-14
期刊：
影响因子：
3.3
通讯作者：
Oksche A
中科院分区：
文献类型：
--
作者：
Plant TD;Zöllner C;Kepura F;Mousa SS;Eichhorst J;Schaefer M;Furkert J;Stein C;Oksche A
内皮素-1（ET-1）既刺激伤害感受器又使它们对伤害性刺激敏感，这种作用可能由感觉神经元中表达的ETA受体（ETAR）介导。这种ET-1介导的作用的细胞机制仅知之甚少。TRPV 1是一种对热、pH和辣椒素敏感的阳离子通道，已知在炎症过程中可被多种细胞介质调节，是ET-1作用的潜在靶点。我们研究了ET-1对背根神经节（DRG）感觉神经元和共表达TRPV 1和ETAR的HEK 293细胞中TRPV 1的影响。在背根神经节膜制备物中检测到特异性125 I-ET-1结合位点（817 ± 92 fmol/mg），ETAR/ETBR比为60：40。在免疫荧光分析中，在初级感觉神经元的亚群中发现TRPV 1和ETAR的共表达。ET-1强烈增强辣椒素诱导的TRPV 1电流在一些神经元，并在HEK 293细胞共表达TRPV 1和ETAR。在共表达TRPV 1和ETBR的HEK 293细胞中观察到较弱的增强作用。ETAR激活也增加了对低pH和热的反应。在HEK 293细胞中，类似于ET-1通过ETAR诱导的TRPV 1的强增强作用可由PKC激活诱导，但不与腺苷酸环化酶或PKA通路的激活剂一起诱导。此外，用双吲哚马来酰亚胺X（BIM X）抑制PKC或突变PKC磷酸化位点S800完全阻止ETAR介导的增强。我们的结论是，ET-1通过PKC依赖性机制增强TRPV 1，这可能在之前研究中描述的ET-1的致痛和痛觉过敏作用中发挥重要作用。
Endothelin-1 (ET-1) both stimulates nociceptors and sensitizes them to noxious stimuli, an effect probably mediated by the ETA receptor (ETAR) expressed in sensory neurons. The cellular mechanisms of this ET-1-mediated effect are only poorly understood. TRPV1, the heat-, pH- and capsaicin-sensitive cation channel already known to be modulated by a number of cellular mediators released in response to noxious stimuli and during inflammation, is a potential target for the action of ET-1. We studied the effects of ET-1 on TRPV1 in sensory neurons from the dorsal root ganglion (DRG) and in HEK293 cells coexpressing TRPV1 and the ETAR. Specific 125I-ET-1 binding sites (817 ± 92 fmol/mg) were detected in membrane preparations of DRG with an ETAR/ETBR ratio of 60:40. In an immunofluorescence analysis, coexpression of TRPV1 and the ETAR was found in a subpopulation of primary sensory neurons. ET-1 strongly potentiated capsaicin-induced TRPV1 currents in some neurons, and in HEK293 cells co-expressing TRPV1 and the ETAR. Weaker potentiation was observed in HEK293 cells coexpressing TRPV1 and the ETBR. ETAR activation also increased responses to low pH and heat. In HEK293 cells, strong potentiation of TRPV1 like that induced by ET-1 via the ETAR could be induced by PKC activation, but not with activators of the adenylyl cyclase or the PKA pathway. Furthermore, inhibition of PKC with bisindolylmaleimide X (BIM X) or mutation of the PKC phosphorylation site S800 completely prevented ETAR-mediated potentiation. We conclude that ET-1 potentiates TRPV1 by a PKC-dependent mechanism and that this could play a major role in the algogenic and hyperalgesic effects of ET-1 described in previous studies.
登录
查看更多内容
影响因子：
4.9
作者：
DAHLOF, B;GUSTAFSSON, D;HANSSON, L
通讯作者：
HANSSON, L
影响因子：
3
作者：
EGUCHI, S;HIRATA, Y;MARUMO, F
通讯作者：
MARUMO, F
影响因子：
64.8
作者：
Chuang, HH;Prescott, ED;Julius, D
通讯作者：
Julius, D
影响因子：
16.2
作者：
Cesare, P;Dekker, LV;McNaughton, PA
通讯作者：
McNaughton, PA
影响因子：
64.8
作者：
ARAI, H;HORI, S;NAKANISHI, S
通讯作者：
NAKANISHI, S