Localizing Drug and Neurotransmitter Receptors in Vivo with Tritium-Labeled Tracers

SummaryParoxetine is a highly potent and selective inhibitor of serotonin reuptake, with in vitro potency greater than that of fluoxetine, fluvoxamine, and sertraline. It has little affinity for a wide variety of neurotransmitter receptors, including catecholaminergic or histaminergic systems, in marked contrast to the tricyclic antidepressants. Paroxetine undergoes first-pass metabolism that is partially saturable to give metabolites that are pharmacologically inactive in vivo, unlike those of fluoxetine or sertraline.

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Excitatory and inhibitory receptors utilize distinct post- and trans-synaptic mechanisms in vivo

eLife ◽

10.7554/elife.59613 ◽

2021 ◽

Vol 10 ◽

Author(s):

Taisuke Miyazaki ◽

Megumi Morimoto-Tomita ◽

Coralie Berthoux ◽

Kotaro Konno ◽

Yoav Noam ◽

...

Keyword(s):

Ampa Receptors ◽

Ectopic Expression ◽

Inhibitory Neurons ◽

Mammalian Brain ◽

Neurotransmitter Receptors ◽

Presynaptic Terminals ◽

Postsynaptic Receptors ◽

A Cell ◽

Synaptic Mechanisms

Ionotropic neurotransmitter receptors at postsynapses mediate fast synaptic transmission upon binding of the neurotransmitter. Post- and trans-synaptic mechanisms through cytosolic, membrane, and secreted proteins have been proposed to localize neurotransmitter receptors at postsynapses. However, it remains unknown which mechanism is crucial to maintain neurotransmitter receptors at postsynapses. In this study, we ablated excitatory or inhibitory neurons in adult mouse brains in a cell-autonomous manner. Unexpectedly, we found that excitatory AMPA receptors remain at the postsynaptic density upon ablation of excitatory presynaptic terminals. In contrast, inhibitory GABAA receptors required inhibitory presynaptic terminals for their postsynaptic localization. Consistent with this finding, ectopic expression at excitatory presynapses of neurexin 3alpha, a putative trans-synaptic interactor with the native GABAA receptor complex, could recruit GABAA receptors to contacted postsynaptic sites. These results establish distinct mechanisms for the maintenance of excitatory and inhibitory postsynaptic receptors in the mature mammalian brain.

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P-4-34 Risperidone compared to novel and reference antipsychotic drugs for the in vivo occupancy of rat brain neurotransmitter receptors

European Neuropsychopharmacology ◽

10.1016/0924-977x(95)90554-q ◽

1995 ◽

Vol 5 (3) ◽

pp. 337

Author(s):

A. Schotte ◽

P.F.M. Janssen ◽

P. Bonaventure ◽

J.E. Leysen

Keyword(s):

Rat Brain ◽

Antipsychotic Drugs ◽

Neurotransmitter Receptors ◽

Brain Neurotransmitter

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GABRP regulates chemokine signalling, macrophage recruitment and tumour progression in pancreatic cancer through tuning KCNN4-mediated Ca2+ signalling in a GABA-independent manner

Gut ◽

10.1136/gutjnl-2018-317479 ◽

2019 ◽

Vol 68 (11) ◽

pp. 1994-2006 ◽

Cited By ~ 10

Author(s):

Shu-Heng Jiang ◽

Li-Li Zhu ◽

Man Zhang ◽

Rong-Kun Li ◽

Qin Yang ◽

...

Keyword(s):

Tumour Progression ◽

Xenograft Model ◽

The Cancer Genome Atlas ◽

Macrophage Infiltration ◽

Ductal Adenocarcinoma ◽

Proximity Ligation Assay ◽

Neurotransmitter Receptors ◽

Gamma Aminobutyric Acid ◽

Independent Manner

Background and aimsPancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death worldwide. Neurotransmitter-initiated signalling pathway is profoundly implicated in tumour initiation and progression. Here, we investigated whether dysregulated neurotransmitter receptors play a role during pancreatic tumourigenesis.MethodsThe Cancer Genome Atlas and Gene Expression Omnibus datasets were used to identify differentially expressed neurotransmitter receptors. The expression pattern of gamma-aminobutyric acid type A receptor pi subunit (GABRP) in human and mouse PDAC tissues and cells was studied by immunohistochemistry and western blot analysis. The in vivo implications of GABRP in PDAC were tested by subcutaneous xenograft model and lung metastasis model. Bioinformatics analysis, transwell experiment and orthotopic xenograft model were used to identify the in vitro and in vivo effects of GABRP on macrophages in PDAC. ELISA, co-immunoprecipitation, proximity ligation assay, electrophysiology, promoter luciferase activity and quantitative real-time PCR analyses were used to identify molecular mechanism.ResultsGABRP expression was remarkably increased in PDAC tissues and associated with poor prognosis, contributed to tumour growth and metastasis. GABRP was correlated with macrophage infiltration in PDAC and pharmacological deletion of macrophages largely abrogated the oncogenic functions of GABRP in PDAC. Mechanistically, GABRP interacted with KCNN4 to induce Ca2+ entry, which leads to activation of nuclear factor κB signalling and ultimately facilitates macrophage infiltration by inducing CXCL5 and CCL20 expression.ConclusionsOverexpressed GABRP exhibits an immunomodulatory role in PDAC in a neurotransmitter-independent manner. Targeting GABRP or its interaction partner KCNN4 may be an effective therapeutic strategy for PDAC.

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Neurexin and Neuroligin-based adhesion complexes drive axonal arborisation growth independent of synaptic activity

10.1101/182808 ◽

2017 ◽

Author(s):

William D Constance ◽

Amrita Mukherjee ◽

Yvette E Fisher ◽

Sînziana Pop ◽

Eric Blanc ◽

...

Keyword(s):

Neural Network ◽

Molecular Mechanisms ◽

Synaptic Activity ◽

Neurotransmitter Receptors ◽

Imaging Studies ◽

Network Function ◽

Branch Growth ◽

Presynaptic Release ◽

The Right

AbstractBuilding arborisations of the right size and shape is fundamental for neural network function. Live imaging studies in vertebrate brains strongly suggest that nascent synapses are critical for branch growth during the development of axonal and dendritic arborisations. The molecular mechanisms underlying such ‘synaptotropic’ events are largely unknown.Here we present a novel system in Drosophila for studying the development of complex axonal arborisations live, in vivo during metamorphosis. In these growing axonal arborisations we see a relationship between the punctate localisations of presynaptic components and branch dynamics that is very similar to synaptotropic growth described in fish and frogs. These presynaptic components however do not appear to represent functional presynaptic release sites and are not paired with clusters of neurotransmitter receptors. Pharmacological and genetic knockdowns of evoked and spontaneous neurotransmission do not impact the outgrowth of these neurons. Instead, we find that axonal branch growth is regulated by the dynamic focal localisations of synaptic adhesion proteins Neurexin and Neuroligin. These adhesion complexes provide selective stability for filopodia by a ‘stick and grow’-based mechanism wholly independent of synaptic activity.

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Neurexin and Neuroligin-based adhesion complexes drive axonal arborisation growth independent of synaptic activity

eLife ◽

10.7554/elife.31659 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 15

Author(s):

William D Constance ◽

Amrita Mukherjee ◽

Yvette E Fisher ◽

Sinziana Pop ◽

Eric Blanc ◽

...

Keyword(s):

Neural Network ◽

Molecular Mechanisms ◽

Synaptic Activity ◽

Neurotransmitter Receptors ◽

Network Function ◽

Branch Growth ◽

Presynaptic Release ◽

The Right ◽

Presynaptic Proteins

Building arborisations of the right size and shape is fundamental for neural network function. Live imaging in vertebrate brains strongly suggests that nascent synapses are critical for branch growth during development. The molecular mechanisms underlying this are largely unknown. Here we present a novel system in Drosophila for studying the development of complex arborisations live, in vivo during metamorphosis. In growing arborisations we see branch dynamics and localisations of presynaptic proteins very similar to the ‘synaptotropic growth’ described in fish/frogs. These accumulations of presynaptic proteins do not appear to be presynaptic release sites and are not paired with neurotransmitter receptors. Knockdowns of either evoked or spontaneous neurotransmission do not impact arbor growth. Instead, we find that axonal branch growth is regulated by dynamic, focal localisations of Neurexin and Neuroligin. These adhesion complexes provide stability for filopodia by a ‘stick-and-grow’ based mechanism wholly independent of synaptic activity.

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Fine Structural Changes in the Microvasculature of the Mouse Pinna: Aging and Radiation Injury

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100050287 ◽

1974 ◽

Vol 32 ◽

pp. 54-55

Author(s):

S. Phyllis Steamer ◽

Rosemarie L. Devine

Keyword(s):

Structural Changes ◽

Radiation Treatment ◽

Arterial Stenosis ◽

Ultrastructural Changes ◽

Vascular Effects ◽

Microvascular Changes ◽

Surrounding Connective Tissue ◽

Fission Neutrons ◽

Total Body

The importance of radiation damage to the skin and its vasculature was recognized by the early radiologists. In more recent studies, vascular effects were shown to involve the endothelium as well as the surrounding connective tissue. Microvascular changes in the mouse pinna were studied in vivo and recorded photographically over a period of 12-18 months. Radiation treatment at 110 days of age was total body exposure to either 240 rad fission neutrons or 855 rad 60Co gamma rays. After in vivo observations in control and irradiated mice, animals were sacrificed for examination of changes in vascular fine structure. Vessels were selected from regions of specific interest that had been identified on photomicrographs. Prominent ultrastructural changes can be attributed to aging as well as to radiation treatment. Of principal concern were determinations of ultrastructural changes associated with venous dilatations, segmental arterial stenosis and tortuosities of both veins and arteries, effects that had been identified on the basis of light microscopic observations. Tortuosities and irregularly dilated vein segments were related to both aging and radiation changes but arterial stenosis was observed only in irradiated animals.

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Induction and Differentiation of Dental Epithelium in Vivo and in Vitro

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100053425 ◽

1982 ◽

Vol 40 ◽

pp. 142-145

Author(s):

E. J. Kollar

Keyword(s):

Connective Tissue ◽

Oral Mucosa ◽

Basal Lamina ◽

Functional Derivatives ◽

Specific Source ◽

Dental Epithelium ◽

Connective Tissue Stroma

The differentiation and maintenance of many specialized epithelial structures are dependent on the underlying connective tissue stroma and on an intact basal lamina. These requirements are especially stringent in the development and maintenance of the skin and oral mucosa. The keratinization patterns of thin or thick cornified layers as well as the appearance of specialized functional derivatives such as hair and teeth can be correlated with the specific source of stroma which supports these differentiated expressions.

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