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H⁺ Permeation and pH Regulation at a Mammalian Serotonin Transporter

Cao, Yongwei and Mager, Sela and Lester, Henry A. (1997) H⁺ Permeation and pH Regulation at a Mammalian Serotonin Transporter. Journal of Neuroscience, 17 (7). pp. 2257-2266. ISSN 0270-6474. PMCID PMC6573487. doi:10.1523/jneurosci.17-07-02257.1997.

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The rat serotonin transporter expressed in Xenopusoocytes displays an inward current in the absence of 5-HT when external pH is lowered to 6.5 or below. The new current differs from the leakage current described previously in two ways. (1) It is ∼10-fold larger at pH 5 than the leakage current at pH 7.5 and reaches 1000 H⁺/sec per transporter at extremes of voltage and pH with no signs of saturation. (2) It is selective for H⁺ by reversal potential measurements. Similar H⁺-induced currents are also observed in several other ion-coupled transporters, including the GABA transporter, the dopamine transporter, and the Na⁺/glucose transporter. The high conductance and high selectivity of the H⁺-induced current suggest that protons may be conducted via a hydrogen-bonded chain (a “proton-wire mechanism”) formed at least partially by side chains within the transporter. In addition, pH affects other conducting states of rat serotonin transporter. Acidic pH potentiates the 5-HT-induced, transport-associated current and inhibits the hyperpolarization-activated transient current. The dose–response relationships for these two effects suggest that two H⁺ binding sites, with pK_a values close to 5.1 and close to 6.3, govern the potentiation of the 5-HT-induced current and the inhibition of the transient current, respectively. These results are important for developing structure-function models that explain permeation properties of neurotransmitter transporters.

Item Type:Article
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URLURL TypeDescription CentralArticle
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 1997 Society for Neuroscience. Received Oct. 15, 1996; revised Jan. 3, 1997; accepted Jan. 7, 1997. This work was supported by grants from the National Institute on Drug Abuse (DA-09121) and the National Institute of Neurological Diseases and Stroke (NS-11756) and by a National Institutes of Health National Research Service Award to Y.C. We thank F. Lin for participating in some of the experiments, M. Sonders for discussing his data with us, and N. Davidson for comments.
Funding AgencyGrant Number
National Institute on Drug AbuseUNSPECIFIED
National Institute of Neurological Disorders and Stroke (NINDS)UNSPECIFIED
NIH Predoctoral FellowshipUNSPECIFIED
Issue or Number:7
PubMed Central ID:PMC6573487
Record Number:CaltechAUTHORS:20191030-144551486
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Official Citation:H+ Permeation and pH Regulation at a Mammalian Serotonin Transporter. Yongwei Cao, Sela Mager, Henry A. Lester. Journal of Neuroscience 1 April 1997, 17 (7) 2257-2266; DOI: 10.1523/JNEUROSCI.17-07-02257.1997
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:99564
Deposited By: Tony Diaz
Deposited On:30 Oct 2019 21:53
Last Modified:16 Nov 2021 17:47

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