Mechanisms of Transient Signaling via Short and Long Prolactin Receptor Isoforms in Female and Male Sensory Neurons
Mechanisms of Transient Signaling via Short and Long Prolactin Receptor Isoforms in Female and Male Sensory Neurons
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DOI：
10.1074/jbc.m113.486571
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发表时间：
2013-11-29
影响因子：
4.8
通讯作者：
Akopian, Armen N.
中科院分区：
文献类型：
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作者：
Belugin, Sergei;Diogenes, Anibal R.;Akopian, Armen N.
背景：催乳素在疼痛情况下调节伤害感受器的活性。结果：催乳素对感觉神经元的调节是急性的，并在催乳素受体短亚型激活后通过 PI3K 和 PKCE 介导。催乳素受体短亚型的作用被长亚型抑制。结论：催乳素受体短亚型介导伤害感受器的短暂敏化。意义：所提出的机制可能是催乳素参与痛觉过敏/疼痛的基础。催乳素（PRL）调节伤害感受器的活性并在疼痛情况下引起痛觉过敏。 PRL 通过快速调节伤害感受器中的通道来增强伤害感受反应。 PRL 诱导神经元瞬时信号传导的分子机制尚不清楚。在这里，我们使用多种细胞生物学和药理学方法来证明，PRL 短暂增强的辣椒素诱发反应涉及雌性大鼠三叉神经元中的蛋白激酶 C E (PKCE) 或磷脂酰肌醇 3-激酶 (PI3K) 通路。接下来，我们通过表达大鼠 PRLR 长异构体 (PRLR-L)、PRLR 短异构体 (PRLR-S) 或两者的混合，在异源表达系统和来自 PRL 受体 (PRLR) 缺失突变小鼠的 TG 神经元中重建了 PRL 诱导的信号传导。结果表明，PRLR-S（而非 PRLR-L）能够介导 PRL 诱导的雄性和雌性 TG 神经元中辣椒素反应的短暂增强。然而，PRLR-L 与 PRLR-S（1:1 比例）的共表达会导致瞬时 PRL 作用受到抑制。 PRLR-L缺失突变体与PRLR-S的共表达表明，与PRLR-L跨膜结构域相邻的细胞质位点负责PRLR-L的抑制作用。此外，原位杂交和免疫组化数据表明，在正常情况下，PRLR-L主要在胶质细胞中表达，在大鼠感觉神经元（3-5%）和人类神经中表达很少。大鼠和人类的 TG 神经元/神经中的主要 PRLR 形式是 PRLR-S。总而言之，感觉神经元中 PRL 诱导的瞬时信号传导由 PI3K 或 PKCE 控制，通过 PRLR-S 同工型介导，而 PRLR-S 介导的瞬时效应会因这些细胞中 PRLR-L 的存在而受到抑制。
Background: Prolactin regulates the activity of nociceptors in pain conditions. Results: Prolactin regulation of sensory neurons is acute and mediated via PI3K and PKCE following activation of prolactin receptor short isoform. Prolactin receptor short isoform actions are inhibited by the long isoform. Conclusion: Prolactin receptor short isoform mediates transient sensitization of nociceptors. Significance: The proposed mechanism could underlie prolactin involvement in hyperalgesia/pain.Prolactin (PRL) regulates activity of nociceptors and causes hyperalgesia in pain conditions. PRL enhances nociceptive responses by rapidly modulating channels in nociceptors. The molecular mechanisms underlying PRL-induced transient signaling in neurons are not well understood. Here we use a variety of cell biology and pharmacological approaches to show that PRL transiently enhanced capsaicin-evoked responses involve protein kinase C E (PKCE) or phosphatidylinositol 3-kinase (PI3K) pathways in female rat trigeminal (TG) neurons. We next reconstituted PRL-induced signaling in a heterologous expression system and TG neurons from PRL receptor (PRLR)-null mutant mice by expressing rat PRLR-long isoform (PRLR-L), PRLR-short isoform (PRLR-S), or a mix of both. Results show that PRLR-S, but not PRLR-L, is capable of mediating PRL-induced transient enhancement of capsaicin responses in both male and female TG neurons. However, co-expression of PRLR-L with PRLR-S (1:1 ratio) leads to the inhibition of the transient PRL actions. Co-expression of PRLR-L deletion mutants with PRLR-S indicated that the cytoplasmic site adjacent to the trans-membrane domain of PRLR-L was responsible for inhibitory effects of PRLR-L. Furthermore, in situ hybridization and immunohistochemistry data indicate that in normal conditions, PRLR-L is expressed mainly in glia with little expression in rat sensory neurons (3-5%) and human nerves. The predominant PRLR form in TG neurons/nerves from rats and humans is PRLR-S. Altogether, PRL-induced transient signaling in sensory neurons is governed by PI3K or PKCE, mediated via the PRLR-S isoform, and transient effects mediated by PRLR-S are inhibited by presence of PRLR-L in these cells.