The serotonin transporter (SERT) and the control of circulating serotonin in teleost fish

硬骨鱼中血清素转运蛋白（SERT）和循环血清素的控制

• 批准号: 1754550
• 负责人: M. Danielle McDonald
• 金额: $ 81.36万
• 依托单位: University of Miami
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1754550&HistoricalAwards=false
• 关键词: serotonin; transporter; SERT; control; circulating

Serotonin is a neurotransmitter most commonly known for its role in depression. In mammals, serotonin can also cause the constriction of blood vessels, altering blood flow to organs throughout the body. Mammalian serotonin transporters in blood platelets remove serotonin from the blood plasma, thereby controlling serotonin's effect on blood vessels. In fishes as in mammals, serotonin levels within the blood plasma are low and elevation of circulating serotonin results in the constriction of blood vessels. However, in contrast to mammals, significant levels of serotonin have not been found within fish blood cells and it is not known how circulating serotonin levels are regulated in fish. This project will fill that gap by characterizing the serotonin transporter's role in controlling circulating levels of serotonin, and thus blood pressure and flow, in fish. Fish will be tested in water with normal oxygen levels, and in low-oxygen conditions when controlling blood flow to active tissues and organs such as the gills is most important. It is expected that this project will reveal the role of serotonin and the serotonin transporter in the control of blood pressure and flow in fish, contributing significantly to the field of cardiovascular physiology. Results may also help to answer existing questions about serotonin's role in blood flow control in mammals. The project will educate and expose underrepresented youth to science, enhance the participation of women and minorities in science, and strengthen collaborative partnerships. The role of the serotonin transporter (SERT) in controlling circulating levels of serotonin (or hydroxytryptamine, 5-HT) and, consequently, vascular resistance, in the Gulf toadfish (Opsanus beta) will be determined under normoxic and hypoxic conditions. Three questions will be addressed: (1) What are the tissue distribution, transport kinetics, and pharmacological sensitivity of a teleost SERT compared to SERT of other vertebrates? (2) What is the role of systemic SERT in the control of circulating 5-HT? (3) What is the role of branchial SERT in the control of circulating 5-HT? The answers to these questions will support the central hypothesis that SERT plays an integral role in controlling circulating 5-HT and, as a result, vascular resistance, blood pressure, and blood flow in teleost fish. Advanced techniques, including fluorescent neurotransmitter imaging probes, will be applied to investigate SERT function at the cellular level. The research will reveal organs, such as the heart, and cell types, such as gill neuroepithelial cells, that are active contributors to 5-HT homeostasis. The potential role of SERT in controlling circulating 5-HT is important because uncontrolled circulating 5-HT levels would lead to an undesirable vasoconstriction of the gill and detrimental reductions in oxygen uptake, an effect that could reduce hypoxia tolerance and limit survival. Project outcomes will also contribute to understanding the possible implications of SERT activation or desensitization with environmental perturbations such as hypoxia and pharmaceutical exposure. The project's educational and outreach impacts include engaging underrepresented youth in marine science and enhancing the participation of women and minorities in science.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

5 -羟色胺是一种神经递质，最广为人知的是它在抑郁症中的作用。在哺乳动物中，血清素也能引起血管收缩，改变血液流向全身各器官。哺乳动物血小板中的血清素转运体将血清素从血浆中移除，从而控制血清素对血管的影响。鱼类和哺乳动物一样，血浆中的血清素水平很低，循环血清素的升高会导致血管收缩。然而，与哺乳动物相比，在鱼类血细胞中没有发现显著水平的血清素，而且尚不清楚鱼类的循环血清素水平是如何调节的。这个项目将通过描述血清素转运体在控制鱼体内血清素循环水平、从而控制血压和血流中的作用来填补这一空白。鱼将在含氧量正常的水中进行测试，在低氧条件下，控制血液流向活跃组织和器官（如鳃）是最重要的。预计本项目将揭示血清素及其转运体在鱼类血压和血流控制中的作用，为心血管生理学领域做出重大贡献。结果也可能有助于回答关于血清素在哺乳动物血液流动控制中的作用的现有问题。该项目将教育代表性不足的青年，让他们接触科学，提高妇女和少数民族对科学的参与，并加强合作伙伴关系。血清素转运体（SERT）在控制循环血清素（或羟色胺，5-HT）水平中的作用，从而在海湾蟾鱼（Opsanus beta）的血管阻力将在常氧和缺氧条件下确定。将解决三个问题：(1)与其他脊椎动物的SERT相比，硬骨鱼SERT的组织分布、运输动力学和药理学敏感性是什么？(2)系统性SERT在控制循环5-羟色胺中的作用是什么？(3)支气管SERT在控制循环5-羟色胺中的作用是什么？这些问题的答案将支持核心假设，即SERT在控制循环5-羟色胺中起着不可或缺的作用，从而控制硬骨鱼的血管阻力、血压和血流量。先进的技术，包括荧光神经递质成像探针，将在细胞水平上研究SERT功能。这项研究将揭示器官，如心脏，和细胞类型，如鳃神经上皮细胞，是5-羟色胺稳态的积极贡献者。SERT在控制循环5-羟色胺中的潜在作用是重要的，因为不受控制的循环5-羟色胺水平将导致鳃血管收缩和有害的氧摄取减少，这种影响可能降低缺氧耐受性并限制生存。项目结果也将有助于理解SERT激活或脱敏与环境扰动（如缺氧和药物暴露）的可能影响。该项目的教育和推广影响包括让代表性不足的青年参与海洋科学，并加强妇女和少数民族对科学的参与。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Mild hypoxia exposure impacts peripheral serotonin uptake and degradation in Gulf toadfish ( Opsanus beta )

轻度缺氧会影响海湾蟾蜍（Opsanus beta）的外周血清素吸收和降解

• DOI: 10.1242/jeb.244064
• 发表时间: 2022
• 期刊: Journal of Experimental Biology
• 影响因子: 2.8
• 作者: Sebastiani, John;Sabatelli, Allyson;McDonald, M. Danielle
• 通讯作者: McDonald, M. Danielle

Pulsatile urea excretion in Gulf toadfish: the role of circulating serotonin and additional 5-HT receptor subtypes

海湾蟾鱼的脉动尿素排泄：循环血清素和其他 5-HT 受体亚型的作用

• DOI: 10.1007/s00360-019-01223-x
• 发表时间: 2019
• 期刊: Journal of Comparative Physiology B
• 作者: Cartolano, Maria C.;Gancel, Haley N.;Lonthair, Joshua;Wood, Chris M.;McDonald, M. Danielle
• 通讯作者: McDonald, M. Danielle

The serotonin transporter and nonselective transporters are involved in peripheral serotonin uptake in the Gulf toadfish, Opsanus beta

血清素转运蛋白和非选择性转运蛋白参与海湾蟾蜍 Opsanus beta 的外周血清素摄取

• DOI: 10.1152/ajpregu.00137.2018
• 发表时间: 2018
• 期刊: Integrative and Comparative Physiology
• 作者: Amador, Molly H.;McDonald, M. Danielle
• 通讯作者: McDonald, M. Danielle

Is serotonin uptake by peripheral tissues sensitive to hypoxia exposure?

外周组织吸收血清素对缺氧敏感吗？

• DOI: 10.1007/s10695-022-01083-3
• 发表时间: 2022
• 期刊: Fish Physiology and Biochemistry
• 影响因子: 2.9
• 作者: Amador, Molly H.;McDonald, M. Danielle
• 通讯作者: McDonald, M. Danielle

The role of uptake and degradation in the regulation of peripheral serotonin dynamics in Gulf toadfish, Opsanus beta

摄取和降解在海湾蟾蜍 Opsanus beta 外周血清素动态调节中的作用

• DOI: 10.1016/j.cbpa.2021.110980
• 发表时间: 2021
• 期刊: Comparative biochemistry and physiology
• 作者: Sebastiani, John;McDonald, M. Danielle
• 通讯作者: McDonald, M. Danielle