The dopamine transporter antiports potassium to increase the uptake of dopamine
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The dopamine transporter antiports potassium to increase the uptake of dopamine. / Schmidt, Solveig G; Malle, Mette Galsgaard; Nielsen, Anne Kathrine; Bohr, Søren S-R; Pugh, Ciara F; Nielsen, Jeppe C; Poulsen, Ida H.; Rand, Kasper D; Hatzakis, Nikos S; Loland, Claus J.
In: Nature Communications, Vol. 13, No. 1, 2446, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - The dopamine transporter antiports potassium to increase the uptake of dopamine
AU - Schmidt, Solveig G
AU - Malle, Mette Galsgaard
AU - Nielsen, Anne Kathrine
AU - Bohr, Søren S-R
AU - Pugh, Ciara F
AU - Nielsen, Jeppe C
AU - Poulsen, Ida H.
AU - Rand, Kasper D
AU - Hatzakis, Nikos S
AU - Loland, Claus J
N1 - © 2022. The Author(s).
PY - 2022
Y1 - 2022
N2 - The dopamine transporter facilitates dopamine reuptake from the extracellular space to terminate neurotransmission. The transporter belongs to the neurotransmitter:sodium symporter family, which includes transporters for serotonin, norepinephrine, and GABA that utilize the Na+ gradient to drive the uptake of substrate. Decades ago, it was shown that the serotonin transporter also antiports K+, but investigations of K+-coupled transport in other neurotransmitter:sodium symporters have been inconclusive. Here, we show that ligand binding to the Drosophila- and human dopamine transporters are inhibited by K+, and the conformational dynamics of the Drosophila dopamine transporter in K+ are divergent from the apo- and Na+-states. Furthermore, we find that K+ increases dopamine uptake by the Drosophila dopamine transporter in liposomes, and visualize Na+ and K+ fluxes in single proteoliposomes using fluorescent ion indicators. Our results expand on the fundamentals of dopamine transport and prompt a reevaluation of the impact of K+ on other transporters in this pharmacologically important family.
AB - The dopamine transporter facilitates dopamine reuptake from the extracellular space to terminate neurotransmission. The transporter belongs to the neurotransmitter:sodium symporter family, which includes transporters for serotonin, norepinephrine, and GABA that utilize the Na+ gradient to drive the uptake of substrate. Decades ago, it was shown that the serotonin transporter also antiports K+, but investigations of K+-coupled transport in other neurotransmitter:sodium symporters have been inconclusive. Here, we show that ligand binding to the Drosophila- and human dopamine transporters are inhibited by K+, and the conformational dynamics of the Drosophila dopamine transporter in K+ are divergent from the apo- and Na+-states. Furthermore, we find that K+ increases dopamine uptake by the Drosophila dopamine transporter in liposomes, and visualize Na+ and K+ fluxes in single proteoliposomes using fluorescent ion indicators. Our results expand on the fundamentals of dopamine transport and prompt a reevaluation of the impact of K+ on other transporters in this pharmacologically important family.
KW - Animals
KW - Dopamine/metabolism
KW - Dopamine Plasma Membrane Transport Proteins/metabolism
KW - Drosophila/metabolism
KW - Ion Transport
KW - Ions/metabolism
KW - Neurotransmitter Agents/metabolism
KW - Potassium/metabolism
KW - Serotonin Plasma Membrane Transport Proteins/metabolism
KW - Sodium/metabolism
KW - Symporters/metabolism
U2 - 10.1038/s41467-022-30154-5
DO - 10.1038/s41467-022-30154-5
M3 - Journal article
C2 - 35508541
VL - 13
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2446
ER -
ID: 305946701