Signaling mechanisms involved in the acute effects of estradiol on 5-HT clearance.
Signaling mechanisms involved in the acute effects of estradiol on 5-HT clearance.
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DOI：
10.1017/s146114571300165x
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发表时间：
2014-05
期刊：
影响因子：
--
通讯作者：
Frazer A
中科院分区：
文献类型：
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作者：
Benmansour S;Privratsky AA;Adeniji OS;Frazer A
以前发现，雌二醇具有抗抑郁样作用，并阻断选择性5-羟色胺再摄取抑制剂（SSRIs）具有抗抑郁样作用的能力。雌二醇的抗抑郁样作用是由于雌激素受体β（ERβ）和/或GPR 30激活，而雌二醇对SSRI作用的阻断是由ERα介导的。本研究的重点是调查信号通路以及相互作用的受体与这两个影响的雌二醇。体内计时电流法用于测量5-羟色胺转运体（SERT）功能。在去卵巢（OVX）大鼠海马CA 3区局部应用雌二醇或选择性ERα（PPT）或ERβ（DPN）激动剂对5-羟色胺（5-HT，serotonin）清除的影响，以及在选择性阻断信号通路或相互作用受体后对氟伏沙明减缓5-HT清除能力的影响。阻断MAPK/ERK 1/2信号通路可阻断雌激素或DPN对ERβ介导的5-HT清除的抑制作用，但对PI 3 K/Akt信号通路无影响。这种作用还涉及与TrkB和IGF-1受体的相互作用。抑制MAPK/ERK 1/2或PI 3 K/Akt信号通路后，Ehrs或PPT对氟伏沙明引起的ERα介导的5-HT清除减慢的抑制作用被阻断。这种效应涉及与IGF-1受体和代谢型谷氨酸受体1的相互作用，但不涉及与TrkB的相互作用。这项研究说明了雌二醇对SERT功能的影响所需的一些信号通路，特别是表明ER亚型引起不同的以及共同的信号通路，为他们的行动。
Estradiol was found previously to have an antidepressant-like effect and to block the ability of selective serotonin reuptake inhibitors (SSRIs) to have an antidepressant-like effect. The antidepressant-like effect of estradiol was due to estrogen receptor β (ERβ) and/or GPR30 activation whereas estradiol’s blockade of the effect of an SSRI was mediated by ERα. This study focuses on investigating signaling pathways as well as interacting receptors associated with these two effects of estradiol. In vivo chronoamperometry was used to measure serotonin transporter (SERT) function. The effect of local application of estradiol or selective agonists for ERα (PPT) or ERβ (DPN) into the CA3 region of the hippocampus of ovariectomized (OVX) rats on 5-hydroxytryptamine (5-HT, serotonin) clearance as well as on the ability of fluvoxamine to slow 5-HT clearance was examined after selective blockade of signaling pathways or that of interacting receptors. Estradiol- or DPN-induced slowing of 5-HT clearance mediated by ERβ was blocked after inhibition of MAPK/ERK1/2 but not of PI3K/Akt signaling pathways. This effect also involved interactions with TrkB, and IGF-1 receptors. Estradiol’s or PPT’s inhibition of the fluvoxamine-induced slowing of 5-HT clearance mediated by ERα, was blocked after inhibition of either MAPK/ERK1/2 or PI3K/Akt signaling pathways. This effect involved interactions with the IGF-1 receptor and with the metabotropic glutamate receptor 1 but not with TrkB. This study illustrates some of the signaling pathways required for the effects of estradiol on SERT function and particularly shows that ER subtypes elicit different as well as common signaling pathways for their actions.