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Amino Acid Residues that Control pH Modulation of Transport-Associated Current in Mammalian Serotonin Transporters

Cao, Yongwei and Li, Ming and Mager, Sela and Lester, Henry A. (1998) Amino Acid Residues that Control pH Modulation of Transport-Associated Current in Mammalian Serotonin Transporters. Journal of Neuroscience, 18 (19). pp. 7739-7749. ISSN 0270-6474. PMCID PMC6793029. doi:10.1523/jneurosci.18-19-07739.1998. https://resolver.caltech.edu/CaltechAUTHORS:20220223-204499000

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Abstract

The rat and human serotonin transporters (rSERT and hSERT, respectively) were expressed in Xenopus oocytes and studied using site-directed mutagenesis, electrophysiological recordings, and [³H]5-HT uptake measurements. rSERT, but not hSERT, displayed increased transport-associated current at low pH. Chimeras and point mutations showed that, of the 52 nonidentical residues, a single residue at position 490 (threonine in rSERT and lysine in hSERT) governs this difference. Furthermore, potentiation required the glutamate residue at position 493. Cysteine substitution and alkylation experiments showed that residue 493 is extracellular. Cysteine at 493 increased, whereas aspartate decreased, the net charge movement per transported 5-HT molecule. The mutations at this region did not significantly affect other aspects of SERT function, including agonist-independent leakage current, voltage-dependent transient current, and H⁺ current. This region may therefore be part of an external gate required for rSERT function. The data and analyses show that, in the absence of detailed structural information, a gate–lumen–gate scheme is useful for interpreting results from mutations that alter functional properties of neurotransmitter transporters.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1523/JNEUROSCI.18-19-07739.1998DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6793029/PubMed CentralArticle
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 1998 Society for Neuroscience. Received June 23, 1998; accepted July 14, 1998. This work was supported by Grant DA-09121 from the National Institute on Drug Abuse and Grant NS-11756 from the National Institute of Neurological Disorders and Stroke, by a National Institutes of Health National Research Service Award to Y.C., and by a National Alliance for Research on Schizophrenia and Depression fellowship to S.M. We thank B. J. Hoffman and G. Rudnick for providing cDNAs.
Funders:
Funding AgencyGrant Number
NIHDA-09121
NIHNS-11756
NIH Predoctoral FellowshipUNSPECIFIED
National Alliance for Research on Schizophrenia and DepressionUNSPECIFIED
Subject Keywords:5-HT; Xenopus oocyte; protons; channels; electrophysiology; sodium
Issue or Number:19
PubMed Central ID:PMC6793029
DOI:10.1523/jneurosci.18-19-07739.1998
Record Number:CaltechAUTHORS:20220223-204499000
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20220223-204499000
Official Citation:Amino Acid Residues that Control pH Modulation of Transport-Associated Current in Mammalian Serotonin Transporters Yongwei Cao, Ming Li, Sela Mager, Henry A. Lester Journal of Neuroscience 1 October 1998, 18 (19) 7739-7749; DOI: 10.1523/JNEUROSCI.18-19-07739.1998
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:113552
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:24 Feb 2022 16:48
Last Modified:24 Feb 2022 16:48

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