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Histamine Receptors Regulate the Activity, Surface Expression, and Phosphorylation of Serotonin Transporters.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-01-22 , DOI: 10.1021/acschemneuro.9b00664 Balasubramaniam Annamalai 1 , Durairaj Ragu Varman 2 , Rebecca E Horton 3 , Lynette C Daws 3 , Lankupalle D Jayanthi 2 , Sammanda Ramamoorthy 2
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-01-22 , DOI: 10.1021/acschemneuro.9b00664 Balasubramaniam Annamalai 1 , Durairaj Ragu Varman 2 , Rebecca E Horton 3 , Lynette C Daws 3 , Lankupalle D Jayanthi 2 , Sammanda Ramamoorthy 2
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Reuptake and clearance of released serotonin (5-HT) are critical in serotonergic neurotransmission. Serotonin transporter (SERT) is mainly responsible for clearing the extracellular 5-HT. Controlled trafficking, phosphorylation, and protein stability have been attributed to robust SERT activity. H3 histamine receptors (H3Rs) act in conjunction and regulate 5-HT release. H3Rs are expressed in the nervous system and located at the serotonergic terminals, where they act as heteroreceptors. Although histaminergic and serotonergic neurotransmissions are thought to be two separate events, whether H3Rs influence SERT in the CNS to control 5-HT reuptake has never been addressed. With a priori knowledge gained from our studies, we explored the possibility of using rat hippocampal synaptosomal preparations. We found that treatment with H3R/H4R-agonists immepip and (R)-(-)-α-methyl-histamine indeed resulted in a time- and concentration-dependent decrease in 5-HT transport. On the other hand, treatment with H3R/H4R-inverse agonist thioperamide caused a moderate increase in 5-HT uptake while blocking the inhibitory effect of H3R/H4R agonists. When investigated further, immepip treatment reduced the level of SERT on the plasma membrane and its phosphorylation. Likewise, CaMKII inhibitor KN93 or calcineurin inhibitor cyclosporine A also inhibited SERT function; however, an additive effect with immepip was not seen. High-speed in vivo chronoamperometry demonstrated that immepip delayed 5-HT clearance while thioperamide accelerated 5-HT clearance from the extracellular space. Immepip selectively inhibited SERT activity in the hippocampus and cortex but not in the striatum, midbrain, and brain stem. Thus, we report here a novel mechanism of regulating SERT activity by H3R-mediated CaMKII/calcineurin pathway in a brain-region-specific manner and perhaps synaptic 5-HT in the CNS that controls 5-HT clearance.
中文翻译：
组胺受体调节5-羟色胺转运蛋白的活性，表面表达和磷酸化。
再摄取和清除释放的血清素（5-HT）在血清素能神经传递中至关重要。血清素转运蛋白（SERT）主要负责清除细胞外5-HT。受控的运输，磷酸化和蛋白质稳定性已归因于强大的SERT活性。H3组胺受体（H3Rs）共同起作用并调节5-HT释放。H3Rs在神经系统中表达并位于血清素能末端，在那里它们充当异源受体。尽管组胺能和5-羟色胺能神经传递被认为是两个独立的事件，但是H3Rs是否影响CNS中的SERT来控制5-HT的再摄取尚未得到解决。从我们的研究中获得先验知识，我们探索了使用大鼠海马突触体制剂的可能性。我们发现用H3R / H4R激动剂immepip和（R）-（-）-α-甲基-组胺治疗确实导致了5-HT转运的时间和浓度依赖性下降。另一方面，用H3R / H4R反向激动剂硫代过酰胺处理可引起5-HT吸收的适度增加，同时阻断H3R / H4R激动剂的抑制作用。当进一步研究时，immepip处理降低了质膜上SERT的水平及其磷酸化。同样，CaMKII抑制剂KN93或钙调神经磷酸酶抑制剂环孢菌素A也抑制SERT功能。但是，未发现有immepip的累加作用。高速体内计时电流法显示，immepip延迟了5-HT的清除，而硫代过酰胺则加速了从细胞外空间清除5-HT的清除。Immepip选择性抑制海马和皮层的SERT活性，但不抑制纹状体，中脑和脑干的SERT活性。因此，我们在这里报告了一种通过H3R介导的CaMKII /钙调神经磷酸酶途径以脑区特异性方式调节SERT活性的新机制，并且可能在控制5-HT清除的中枢神经系统中突触5-HT。
更新日期：2020-01-23
中文翻译：
组胺受体调节5-羟色胺转运蛋白的活性，表面表达和磷酸化。
再摄取和清除释放的血清素（5-HT）在血清素能神经传递中至关重要。血清素转运蛋白（SERT）主要负责清除细胞外5-HT。受控的运输，磷酸化和蛋白质稳定性已归因于强大的SERT活性。H3组胺受体（H3Rs）共同起作用并调节5-HT释放。H3Rs在神经系统中表达并位于血清素能末端，在那里它们充当异源受体。尽管组胺能和5-羟色胺能神经传递被认为是两个独立的事件，但是H3Rs是否影响CNS中的SERT来控制5-HT的再摄取尚未得到解决。从我们的研究中获得先验知识，我们探索了使用大鼠海马突触体制剂的可能性。我们发现用H3R / H4R激动剂immepip和（R）-（-）-α-甲基-组胺治疗确实导致了5-HT转运的时间和浓度依赖性下降。另一方面，用H3R / H4R反向激动剂硫代过酰胺处理可引起5-HT吸收的适度增加，同时阻断H3R / H4R激动剂的抑制作用。当进一步研究时，immepip处理降低了质膜上SERT的水平及其磷酸化。同样，CaMKII抑制剂KN93或钙调神经磷酸酶抑制剂环孢菌素A也抑制SERT功能。但是，未发现有immepip的累加作用。高速体内计时电流法显示，immepip延迟了5-HT的清除，而硫代过酰胺则加速了从细胞外空间清除5-HT的清除。Immepip选择性抑制海马和皮层的SERT活性，但不抑制纹状体，中脑和脑干的SERT活性。因此，我们在这里报告了一种通过H3R介导的CaMKII /钙调神经磷酸酶途径以脑区特异性方式调节SERT活性的新机制，并且可能在控制5-HT清除的中枢神经系统中突触5-HT。
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