Unifying concept of serotonin transporter-associated currents |
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Authors: | Schicker Klaus Uzelac Zeljko Gesmonde Joan Bulling Simon Stockner Thomas Freissmuth Michael Boehm Stefan Rudnick Gary Sitte Harald H Sandtner Walter |
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Affiliation: | Center of Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria. |
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Abstract: | Serotonin (5-HT) uptake by the human serotonin transporter (hSERT) is driven by ion gradients. The stoichiometry of transported 5-HT and ions is predicted to result in electroneutral charge movement. However, hSERT mediates a current when challenged with 5-HT. This discrepancy can be accounted for by an uncoupled ion flux. Here, we investigated the mechanistic basis of the uncoupled currents and its relation to the conformational cycle of hSERT. Our observations support the conclusion that the conducting state underlying the uncoupled ion flux is in equilibrium with an inward facing state of the transporter with K+ bound. We identified conditions associated with accumulation of the transporter in inward facing conformations. Manipulations that increased the abundance of inward facing states resulted in enhanced steady-state currents. We present a comprehensive kinetic model of the transport cycle, which recapitulates salient features of the recorded currents. This study provides a framework for exploring transporter-associated currents. |
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Keywords: | Membrane Transport Monoamine Transporters Neurotransmitter Transport Neurotransmitters Serotonin Transporters |
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