Heterogeneities in Axonal Structure and Transporter Distribution Lower Dopamine Reuptake Efficiency
| Autor: | Cihan Kaya, Ethan R. Block, James R. Faeder, Mary Hongying Cheng, Terrence J. Sejnowski, Alexander Sorkin, Thomas M. Bartol, Ivet Bahar |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
spatial simulation
Protein Conformation Dopamine Population Action Potentials Mice Transgenic Molecular Dynamics Simulation Novel Tools and Methods Synaptic Transmission Reuptake Synapse Tissue Culture Techniques 03 medical and health sciences 0302 clinical medicine stochastics Dopamine reuptake medicine Animals Humans Axon education dopamine transporter 030304 developmental biology Dopamine transporter 0303 health sciences education.field_of_study Dopamine Plasma Membrane Transport Proteins biology Chemistry General Neuroscience Dopaminergic Neurons Dopaminergic Brain Transporter General Medicine New Research Axons medicine.anatomical_structure nervous system 7.1 Biophysics biology.protein 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | eNeuro |
| ISSN: | 2373-2822 |
| Popis: | Efficient clearance of dopamine (DA) from the synapse is key to regulating dopaminergic signaling. This role is fulfilled by DA transporters (DATs). Recent advances in the structural characterization of DAT fromDrosophila(dDAT) and in high-resolution imaging of DA neurons and the distribution of DATs in living cells now permit us to gain a mechanistic understanding of DA reuptake eventsin silico. Using electron microscopy images and immunofluorescence of transgenic knock-in mouse brains that express hemagglutinin-tagged DAT in DA neurons, we reconstructed a realistic environment for MCell simulations of DA reuptake, wherein the identity, population and kinetics of homology-modeled human DAT (hDAT) substates were derived from molecular simulations. The complex morphology of axon terminals near active zones was observed to give rise to large variations in DA reuptake efficiency, and thereby in extracellular DA density. Comparison of the effect of different firing patterns showed that phasic firing would increase the probability of reaching local DA levels sufficiently high to activate low-affinity DA receptors, mainly owing to high DA levels transiently attained during the burst phase. The experimentally observed nonuniform surface distribution of DATs emerged as a major modulator of DA signaling: reuptake was slower, and the peaks/width of transient DA levels were sharper/wider under nonuniform distribution of DATs, compared with uniform. Overall, the study highlights the importance of accurate descriptions of extrasynaptic morphology, DAT distribution, and conformational kinetics for quantitative evaluation of dopaminergic transmission and for providing deeper understanding of the mechanisms that regulate DA transmission. |
| Databáze: | OpenAIRE |
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