Nanoscopic dopamine transporter distribution and conformation are inversely regulated by excitatory drive and D2 autoreceptor activity

Matthew D. Lycas, Aske L. Ejdrup, Andreas T. Sørensen, Nicolai O. Haahr, Søren H. Jørgensen, Daryl A. Guthrie, Jonatan F. Støier, Christian Werner, Amy Hauck Newman, Markus Sauer, Freja Herborg, Ulrik Gether*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

10 Citations (Scopus)
15 Downloads (Pure)

Abstract

The nanoscopic organization and regulation of individual molecular components in presynaptic varicosities of neurons releasing modulatory volume neurotransmitters like dopamine (DA) remain largely elusive. Here we show, by application of several super-resolution microscopy techniques to cultured neurons and mouse striatal slices, that the DA transporter (DAT), a key protein in varicosities of dopaminergic neurons, exists in the membrane in dynamic equilibrium between an inward-facing nanodomain-localized and outward-facing unclustered configuration. The balance between these configurations is inversely regulated by excitatory drive and DA D2 autoreceptor activation in a manner dependent on Ca2+ influx via N-type voltage-gated Ca2+ channels. The DAT nanodomains contain tens of transporters molecules and overlap with nanodomains of PIP2 (phosphatidylinositol-4,5-bisphosphate) but show little overlap with D2 autoreceptor, syntaxin-1, and clathrin nanodomains. The data reveal a mechanism for rapid alterations of nanoscopic DAT distribution and show a striking link of this to the conformational state of the transporter.

Original languageEnglish
Article number111431
JournalCell Reports
Volume40
Issue number13
Number of pages27
ISSN2211-1247
DOIs
Publication statusPublished - 2022

Bibliographical note

Publisher Copyright:
© 2022

Keywords

  • CP: Neuroscience
  • dopamine receptors
  • dopamine transporter
  • fluorescent cocaine analogues
  • nanodomains
  • neurotransmitter transporters
  • PIP2
  • super-resolution microscopy
  • synaptic architecture
  • volume transmission

Cite this