Nanoscopic dopamine transporter distribution and conformation are inversely regulated by excitatory drive and D2 autoreceptor activity
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Nanoscopic dopamine transporter distribution and conformation are inversely regulated by excitatory drive and D2 autoreceptor activity. / Lycas, Matthew D.; Ejdrup, Aske L.; Sørensen, Andreas T.; Haahr, Nicolai O.; Jørgensen, Søren H.; Guthrie, Daryl A.; Støier, Jonatan F.; Werner, Christian; Newman, Amy Hauck; Sauer, Markus; Herborg, Freja; Gether, Ulrik.
I: Cell Reports, Bind 40, Nr. 13, 111431, 2022.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Nanoscopic dopamine transporter distribution and conformation are inversely regulated by excitatory drive and D2 autoreceptor activity
AU - Lycas, Matthew D.
AU - Ejdrup, Aske L.
AU - Sørensen, Andreas T.
AU - Haahr, Nicolai O.
AU - Jørgensen, Søren H.
AU - Guthrie, Daryl A.
AU - Støier, Jonatan F.
AU - Werner, Christian
AU - Newman, Amy Hauck
AU - Sauer, Markus
AU - Herborg, Freja
AU - Gether, Ulrik
N1 - Publisher Copyright: © 2022
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - CP: Neuroscience
KW - dopamine receptors
KW - dopamine transporter
KW - fluorescent cocaine analogues
KW - nanodomains
KW - neurotransmitter transporters
KW - PIP2
KW - super-resolution microscopy
KW - synaptic architecture
KW - volume transmission
U2 - 10.1016/j.celrep.2022.111431
DO - 10.1016/j.celrep.2022.111431
M3 - Journal article
C2 - 36170827
AN - SCOPUS:85138825773
VL - 40
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 13
M1 - 111431
ER -
ID: 322283247