A link between plasma membrane calcium ATPase 2 (PMCA2), estrogen and estrogen receptor α signaling in mechanical pain
A link between plasma membrane calcium ATPase 2 (PMCA2), estrogen and estrogen receptor α signaling in mechanical pain
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DOI：
10.1038/s41598-018-35263-0
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发表时间：
2018-11-22
影响因子：
4.6
通讯作者：
Elkabes, Stella
中科院分区：
文献类型：
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作者：
Khariv, Veronika;Acioglu, Cigdem;Elkabes, Stella
早期对转基因小鼠的研究表明，质膜钙ATP酶2（PMCA 2），一种钙挤出泵，在机械性疼痛反应中起着一种新的性别依赖性作用：与雌性PMCA 2（+/+）小鼠相比，雌性而非雄性PMCA 2（+/-）小鼠表现出更强的机械性疼痛。本研究的目的是确定卵巢类固醇对PMCA 2（+/+）与PMCA 2（+/-）小鼠中基因型和性别依赖性机械性疼痛表现的贡献。卵巢切除术增加了PMCA 2（+/+）小鼠的机械疼痛敏感性，17 β-雌二醇（E2）替代使其恢复到基础水平，但在PMCA 2（+/-）同窝出生小鼠中没有。鞘内注射雌激素受体α（ER α）激动剂可诱导雌性PMCA 2（+/+）小鼠背角（DH）中的ER α信号传导，但对PMCA 2（+/-）小鼠无效。在雄性PMCA 2（+/+）和PMCA 2（+/-）小鼠中，睾丸切除术后E2处理未重现在雌性中观察到的基因型依赖性差异疼痛反应，激动剂未引发ER α信号传导。这些发现在PMCA 2、ER α和机械性疼痛之间建立了一种新的女性特异性联系。据推测，PMCA 2对于雌性DH中足够的ER α信号传导是必不可少的，并且雌性PMCA 2（+/-）小鼠中受损的ER α信号传导阻碍了E2的镇痛作用，导致对机械刺激的敏感性增加。
Earlier studies on genetically modified mice indicated that plasma membrane calcium ATPase 2 (PMCA2), a calcium extrusion pump, plays a novel and sex-dependent role in mechanical pain responses: female, but not male, PMCA2(+/-) mice manifest increased mechanical pain compared to female PMCA2(+/+) mice. The goal of the present studies was to determine the contribution of ovarian steroids to the genotype-and sex-dependent manifestation of mechanical pain in PMCA2(+/+) versus PMCA2(+/-) mice. Ovariectomy increased mechanical pain sensitivity and 17 beta-estradiol (E2) replacement restored it to basal levels in PMCA2(+/+) mice, but not in PMCA2(+/-) littermates. Intrathecal administration of an estrogen receptor alpha (ER alpha) agonist induced ER alpha signaling in the dorsal horn (DH) of female PMCA2(+/+) mice, but was ineffective in PMCA2(+/-) mice. In male PMCA2(+/+) and PMCA2(+/-) mice, E2 treatment following orchidectomy did not recapitulate the genotype-dependent differential pain responses observed in females and the agonist did not elicit ER alpha signaling. These findings establish a novel, female-specific link between PMCA2, ER alpha and mechanical pain. It is postulated that PMCA2 is essential for adequate ERa signaling in the female DH and that impaired ER alpha signaling in the female PMCA2(+/-) mice hinders the analgesic effects of E2 leading to increased sensitivity to mechanical stimuli.