Divergence in endothelin-1- and bradykinin-activated store-operated calcium entry in afferent sensory neurons.
Divergence in endothelin-1- and bradykinin-activated store-operated calcium entry in afferent sensory neurons.
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DOI：
10.1177/1759091415578714
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发表时间：
2015-03
期刊：
影响因子：
4.7
通讯作者：
Jeske NA
中科院分区：
文献类型：
--
作者：
Szteyn K;Gomez R;Berg KA;Jeske NA
内皮素-1（ET-1）和缓激肽（BK）是通过Gαq/11-蛋白偶联受体（GPCRs）传递信号的内源性肽，产生伤害感受器敏化和疼痛。这两种肽激活磷脂酶C，以刺激Ca 2+积累，二酰甘油的生产，和蛋白激酶C激活，并通过G蛋白受体激酶2依赖性机制迅速脱敏。然而，在多种模型中，ET-1产生比BK更大的反应和更持久的伤害性行为，表明初级传入感觉神经元中的潜在分歧信号传导机制。使用培养的感觉神经元，我们表现出显着的差异，Ca 2+内流和Ca 2+释放从细胞内存储后ET-1和BK治疗。由于细胞内钙池耗竭可能有助于调节GPCR下游的其他信号级联反应，因此我们将研究集中在钙池操纵的钙通道上。使用药理学方法，我们确定瞬时受体电位典型通道3（TRPC 3）作为一个主要贡献者的Ca 2+内流后ET-1治疗。另一方面，BK处理刺激了Orai 1的激活，而TRPC 3的输入很少。综上所述，本文提供的数据表明，ET-1信号传导靶向TRPC 3，产生延长的Ca 2+信号，使伤害性反应持续存在。相反，Orai 1作为BK受体激活的下游靶点占主导地位，并导致短暂的细胞内Ca 2+增加和缩短的伤害性反应。
Endothelin-1 (ET-1) and bradykinin (BK) are endogenous peptides that signal through Gαq/11-protein coupled receptors (GPCRs) to produce nociceptor sensitization and pain. Both peptides activate phospholipase C to stimulate Ca2+ accumulation, diacylglycerol production, and protein kinase C activation and are rapidly desensitized via a G-protein receptor kinase 2-dependent mechanism. However, ET-1 produces a greater response and longer lasting nocifensive behavior than BK in multiple models, indicating a potentially divergent signaling mechanism in primary afferent sensory neurons. Using cultured sensory neurons, we demonstrate significant differences in both Ca2+ influx and Ca2+ release from intracellular stores following ET-1 and BK treatments. As intracellular store depletion may contribute to the regulation of other signaling cascades downstream of GPCRs, we concentrated our investigation on store-operated Ca2+ channels. Using pharmacological approaches, we identified transient receptor potential canonical channel 3 (TRPC3) as a dominant contributor to Ca2+ influx subsequent to ET-1 treatment. On the other hand, BK treatment stimulated Orai1 activation, with only minor input from TRPC3. Taken together, data presented here suggest that ET-1 signaling targets TRPC3, generating a prolonged Ca2+ signal that perpetuates nocifensive responses. In contrast, Orai1 dominates as the downstream target of BK receptor activation and results in transient intracellular Ca2+ increases and abridged nocifensive responses.
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DOI：
10.1523/jneurosci.5053-10.2011
发表时间：
2011-03-09
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Gemes G;Bangaru ML;Wu HE;Tang Q;Weihrauch D;Koopmeiners AS;Cruikshank JM;Kwok WM;Hogan QH
通讯作者：
Hogan QH
影响因子：
5.3
作者：
Gamper, N;Reznikov, V;Shapiro, MS
通讯作者：
Shapiro, MS
影响因子：
3.5
作者：
Horinouchi, Takahiro;Terada, Koji;Miwa, Soichi
通讯作者：
Miwa, Soichi
影响因子：
3.1
作者：
Krzyzanowska, Agnieszka;Avendano, Carlos
通讯作者：
Avendano, Carlos
影响因子：
16.2
作者：
EWALD, DA;PANG, IH;MILLER, RJ
通讯作者：
MILLER, RJ