Handling of intracellular K+ determines voltage dependence of plasmalemmal monoamine transporter function

Author:

Bhat Shreyas1ORCID,Niello Marco1,Schicker Klaus2,Pifl Christian3,Sitte Harald H1ORCID,Freissmuth Michael1,Sandtner Walter1ORCID

Affiliation:

1. Institute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

2. Division of Neurophysiology and Neuropharmacology, Centre for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

3. Center for Brain Research, Medical University of Vienna, Vienna, Austria

Abstract

The concentrative power of the transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT) is thought to be fueled by the transmembrane Na+ gradient, but it is conceivable that they can also tap other energy sources, for example, membrane voltage and/or the transmembrane K+ gradient. We have addressed this by recording uptake of endogenous substrates or the fluorescent substrate APP+(4-(4-dimethylamino)phenyl-1-methylpyridinium) under voltage control in cells expressing DAT, NET, or SERT. We have shown that DAT and NET differ from SERT in intracellular handling of K+. In DAT and NET, substrate uptake was voltage-dependent due to the transient nature of intracellular K+ binding, which precluded K+ antiport. SERT, however, antiports K+ and achieves voltage-independent transport. Thus, there is a trade-off between maintaining constant uptake and harvesting membrane potential for concentrative power, which we conclude to occur due to subtle differences in the kinetics of co-substrate ion binding in closely related transporters.

Funder

Austrian Science Fund

Vienna Science and Technology Fund

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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