Super-resolution microscopy reveals functional organization of dopamine transporters into cholesterol and neuronal activity-dependent nanodomains

Troels Rahbek-Clemmensen, Matthew D. Lycas, Simon Erlendsson, Jacob Eriksen, Mia Apuschkin, Frederik Vilhardt, Trine N. Jørgensen, Freja H. Hansen and Ulrik Gether ()
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Troels Rahbek-Clemmensen: University of Copenhagen
Matthew D. Lycas: University of Copenhagen
Simon Erlendsson: University of Copenhagen
Jacob Eriksen: University of Copenhagen
Mia Apuschkin: University of Copenhagen
Frederik Vilhardt: University of Copenhagen
Trine N. Jørgensen: University of Copenhagen
Freja H. Hansen: University of Copenhagen
Ulrik Gether: University of Copenhagen

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Dopamine regulates reward, cognition, and locomotor functions. By mediating rapid reuptake of extracellular dopamine, the dopamine transporter is critical for spatiotemporal control of dopaminergic neurotransmission. Here, we use super-resolution imaging to show that the dopamine transporter is dynamically sequestrated into cholesterol-dependent nanodomains in the plasma membrane of presynaptic varicosities and neuronal projections of dopaminergic neurons. Stochastic optical reconstruction microscopy reveals irregular dopamine transporter nanodomains (∼70 nm mean diameter) that were highly sensitive to cholesterol depletion. Live photoactivated localization microscopy shows a similar dopamine transporter membrane organization in live heterologous cells. In neurons, dual-color dSTORM shows that tyrosine hydroxylase and vesicular monoamine transporter-2 are distinctively localized adjacent to, but not overlapping with, the dopamine transporter nanodomains. The molecular organization of the dopamine transporter in nanodomains is reversibly reduced by short-term activation of NMDA-type ionotropic glutamate receptors, implicating dopamine transporter nanodomain distribution as a potential mechanism to modulate dopaminergic neurotransmission in response to excitatory input.

Date: 2017
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DOI: 10.1038/s41467-017-00790-3

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