Essential role of Ret for defining non-peptidergic nociceptor phenotypes and functions in the adult mouse
Essential role of Ret for defining non-peptidergic nociceptor phenotypes and functions in the adult mouse
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DOI：
10.1111/j.1460-9568.2011.07634.x
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发表时间：
2011-04-01
影响因子：
3.4
通讯作者：
Ernfors, Patrik
中科院分区：
文献类型：
--
作者：
Franck, Marina C. M.;Stenqvist, Anna;Ernfors, Patrik
痛觉性感觉神经元表达的特殊离子通道和受体的激活介导了有害刺激后疼痛的转导。一种常见的表达神经生长因子受体TrkA的早期伤害感受亚系在出生前后分化为多肽性和非多肽性伤害感受受体。在这一过程中，肽能神经元维持TrkA的表达，而非肽能神经元下调TrkA，上调常见胶质源性神经营养因子家族配体受体Ret，并结合隔离素B4 （IB4）。虽然Ret可以对伤害神经元的分子和生理特性产生深远的影响，但其作用尚不完全清楚。在这里，我们删除了中小型感觉神经元中的Ret，绕过了完全Ret敲除的早期致命性。我们发现Ret在两个不同的中小型非肽能神经元群体中表达，一个IB4+和一个IB4-群体。在这些神经元中，Ret是几种离子通道和受体的关键调节剂，包括Nav1.8、Nav1.9、ASIC2a、P2X3、TrpC3、TrpM8、TrpA1、δ阿片受体、MrgD、MrgA1和MrgB4。ret缺乏的小鼠对芥子气诱导的神经源性炎症没有反应，有升高的基础反应，不能终止损伤诱导的对冷刺激的敏化，对基础但不是损伤诱导的机械刺激的超敏，而热感觉基本完好。我们认为，疼痛反应的升高可能与GPR35有关，而GPR35在成年ret缺乏小鼠中是失调的。我们的研究结果表明，Ret对参与感觉刺激检测和转导的几种分子底物的表达至关重要，导致Ret缺乏后的生理改变。
Transduction of pain following noxious stimuli is mediated by the activation of specialized ion channels and receptors expressed by nociceptive sensory neurons. A common early nociceptive sublineage expressing the nerve growth factor receptor TrkA diversifies into peptidergic and non-peptidergic nociceptors around birth. In this process, peptidergic neurons maintain TrkA expression, while non-peptidergic neurons downregulate TrkA and upregulate the common glial-derived neurotrophic factor family ligand receptor Ret and bind the isolectin B4 (IB4). Although Ret can have profound impacts on the molecular and physiological properties of nociceptive neurons, its role is not fully understood. Here we have deleted Ret in small- and medium-size sensory neurons, bypassing the early lethality of the full Ret knockout. We identify that Ret is expressed in two distinct populations of small-medium sized non-peptidergic neurons, an IB4+ and an IB4- population. In these neurons, Ret is a critical regulator of several ion channels and receptors, including Nav1.8, Nav1.9, ASIC2a, P2X3, TrpC3, TrpM8, TrpA1, delta opioid receptor, MrgD, MrgA1 and MrgB4. Ret-deficient mice fail to respond to mustard oil-induced neurogenic inflammation, have elevated basal responses and a failure to terminate injury-induced sensitization to cold stimuli, hypersensitivity to basal but not injury-induced mechanical stimuli, while heat sensation is largely intact. We propose that elevated pain responses could be contributed by GPR35, which is dysregulated in adult Ret-deficient mice. Our results show that Ret is critical for expression of several molecular substrates participating in the detection and transduction of sensory stimuli, resulting in altered physiology following Ret deficiency.