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Title: Activity and subcellular trafficking of the sodium-coupled choline transporter CHT is regulated acutely by peroxynitrite
Authors: Metta Pinthong
Stefanie A G Black
Fabiola M. Ribeiro
Chumpol Pholpramool
Stephen S G Ferguson
Rebecca Jane Rylett
Western University
Robarts Research Institute
Mahidol University
Keywords: Pharmacology, Toxicology and Pharmaceutics
Issue Date: 1-Mar-2008
Citation: Molecular Pharmacology. Vol.73, No.3 (2008), 801-812
Abstract: Excess formation of nitric oxide and superoxide by-products (peroxynitrite, reactive oxygen, and reactive nitrogen species) attenuates cholinergic transmission potentially having a role in Alzheimer disease pathogenesis. In this study, we investigated mechanisms by which acute exposure to peroxynitrite impairs function of the sodium-dependent hemicholinium-3 (HC-3)-sensitive choline transporter (CHT) that provides substrate for acetylcholine synthesis. The peroxynitrite generator 3-morpholinosydnonimine (SIN-1) acutely inhibited choline uptake in cells stably expressing FLAG-tagged rat CHT in a dose- and time-dependent manner, with an IC50 = 0.9 ± 0.14 mM and t 1/2 = 4 min. SIN-1 significantly reduced Vmax of choline uptake without altering the Km. This correlated with a SIN-1-induced decrease in cell surface CHT protein, observed as lowered levels of HC-3 binding and biotinylated CHT at the plasma membrane. It is noteworthy that short-term exposure of cells to SIN-1 accelerated the rate of internalization of CHT from the plasma membrane, but it did not alter return of CHT back to the cell surface. SIN-1 did not disrupt cell membrane integrity or cause cell death. Thus, the inhibitory effect of SIN-1 on choline uptake activity and HC-3 binding was related to enhanced internalization of CHT proteins from the plasma membrane to subcellular organelles. Copyright © 2008 The American Society for Pharmacology and Experimental Therapeutics.
ISSN: 15210111
Appears in Collections:Scopus 2006-2010

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