A Novel Biotinylated Homotryptamine Derivative for Quantum Dot Imaging of Serotonin Transporter in Live Cells

The serotonin transporter (SERT) is the primary target for selective serotonin reuptake inhibitor (SSRI) antidepressants that are thought to exert their therapeutic effects by increasing the synaptic concentration of serotonin. Consequently, probes that can be utilized to study cellular trafficking...

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Autores principales:	Ian D. Tomlinson, Oleg Kovtun, Ruben Torres, Laurel G. Bellocchio, Travis Josephs, Sandra J. Rosenthal
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	serotonin transporter ligand quantum dot labeling single particle tracking Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/32437af905a24b7bb07c718772412d08
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spelling	oai:doaj.org-article:32437af905a24b7bb07c718772412d082021-11-18T08:20:09ZA Novel Biotinylated Homotryptamine Derivative for Quantum Dot Imaging of Serotonin Transporter in Live Cells1662-510210.3389/fncel.2021.667044https://doaj.org/article/32437af905a24b7bb07c718772412d082021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fncel.2021.667044/fullhttps://doaj.org/toc/1662-5102The serotonin transporter (SERT) is the primary target for selective serotonin reuptake inhibitor (SSRI) antidepressants that are thought to exert their therapeutic effects by increasing the synaptic concentration of serotonin. Consequently, probes that can be utilized to study cellular trafficking of SERT are valuable research tools. We have developed a novel ligand (IDT785) that is composed of a SERT antagonist (a tetrahydro pyridyl indole derivative) conjugated to a biotinylated poly ethylene glycol (PEG) via a phenethyl linker. This compound was determined to be biologically active and inhibited SERT-mediated reuptake of IDT307 with the half-maximal inhibitory concentration of 7.2 ± 0.3 μM. We demonstrated that IDT785 enabled quantum dot (QD) labeling of membrane SERT in transfected HEK-293 cultures that could be blocked using the high affinity serotonin reuptake inhibitor paroxetine. Molecular docking studies suggested that IDT785 might be binding to the extracellular vestibule binding site rather than the orthosteric substrate binding site, which could be attributable to the hydrophilicity of the PEG chain and the increased loss of degrees of freedom that would be required to penetrate into the orthosteric binding site. Using IDT785, we were able to study the membrane localization and membrane dynamics of YFP-SERT heterologously expressed in HEK-293 cells and demonstrated that SERT expression was enriched in the membrane edge and in thin cellular protrusions.Ian D. TomlinsonOleg KovtunRuben TorresRuben TorresLaurel G. BellocchioTravis JosephsSandra J. RosenthalSandra J. RosenthalSandra J. RosenthalSandra J. RosenthalSandra J. RosenthalSandra J. RosenthalFrontiers Media S.A.articleserotonin transporterligandquantum dotlabelingsingle particle trackingNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENFrontiers in Cellular Neuroscience, Vol 15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	serotonin transporter ligand quantum dot labeling single particle tracking Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	serotonin transporter ligand quantum dot labeling single particle tracking Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Ian D. Tomlinson Oleg Kovtun Ruben Torres Ruben Torres Laurel G. Bellocchio Travis Josephs Sandra J. Rosenthal Sandra J. Rosenthal Sandra J. Rosenthal Sandra J. Rosenthal Sandra J. Rosenthal Sandra J. Rosenthal A Novel Biotinylated Homotryptamine Derivative for Quantum Dot Imaging of Serotonin Transporter in Live Cells
description	The serotonin transporter (SERT) is the primary target for selective serotonin reuptake inhibitor (SSRI) antidepressants that are thought to exert their therapeutic effects by increasing the synaptic concentration of serotonin. Consequently, probes that can be utilized to study cellular trafficking of SERT are valuable research tools. We have developed a novel ligand (IDT785) that is composed of a SERT antagonist (a tetrahydro pyridyl indole derivative) conjugated to a biotinylated poly ethylene glycol (PEG) via a phenethyl linker. This compound was determined to be biologically active and inhibited SERT-mediated reuptake of IDT307 with the half-maximal inhibitory concentration of 7.2 ± 0.3 μM. We demonstrated that IDT785 enabled quantum dot (QD) labeling of membrane SERT in transfected HEK-293 cultures that could be blocked using the high affinity serotonin reuptake inhibitor paroxetine. Molecular docking studies suggested that IDT785 might be binding to the extracellular vestibule binding site rather than the orthosteric substrate binding site, which could be attributable to the hydrophilicity of the PEG chain and the increased loss of degrees of freedom that would be required to penetrate into the orthosteric binding site. Using IDT785, we were able to study the membrane localization and membrane dynamics of YFP-SERT heterologously expressed in HEK-293 cells and demonstrated that SERT expression was enriched in the membrane edge and in thin cellular protrusions.
format	article
author	Ian D. Tomlinson Oleg Kovtun Ruben Torres Ruben Torres Laurel G. Bellocchio Travis Josephs Sandra J. Rosenthal Sandra J. Rosenthal Sandra J. Rosenthal Sandra J. Rosenthal Sandra J. Rosenthal Sandra J. Rosenthal
author_facet	Ian D. Tomlinson Oleg Kovtun Ruben Torres Ruben Torres Laurel G. Bellocchio Travis Josephs Sandra J. Rosenthal Sandra J. Rosenthal Sandra J. Rosenthal Sandra J. Rosenthal Sandra J. Rosenthal Sandra J. Rosenthal
author_sort	Ian D. Tomlinson
title	A Novel Biotinylated Homotryptamine Derivative for Quantum Dot Imaging of Serotonin Transporter in Live Cells
title_short	A Novel Biotinylated Homotryptamine Derivative for Quantum Dot Imaging of Serotonin Transporter in Live Cells
title_full	A Novel Biotinylated Homotryptamine Derivative for Quantum Dot Imaging of Serotonin Transporter in Live Cells
title_fullStr	A Novel Biotinylated Homotryptamine Derivative for Quantum Dot Imaging of Serotonin Transporter in Live Cells
title_full_unstemmed	A Novel Biotinylated Homotryptamine Derivative for Quantum Dot Imaging of Serotonin Transporter in Live Cells
title_sort	novel biotinylated homotryptamine derivative for quantum dot imaging of serotonin transporter in live cells
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/32437af905a24b7bb07c718772412d08
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A Novel Biotinylated Homotryptamine Derivative for Quantum Dot Imaging of Serotonin Transporter in Live Cells

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