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Published April 1, 1997 | Published
Journal Article Open

H⁺ Permeation and pH Regulation at a Mammalian Serotonin Transporter

Abstract

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.

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.

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August 19, 2023
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