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Volume 17, Number 7, Issue of April 1, 1997 pp. 2257-2266
Copyright ©1997 Society for NeuroscienceH+ Permeation and pH Regulation at a Mammalian Serotonin Transporter
Received Oct. 15, 1996; revised Jan. 3, 1997; accepted Jan. 7, 1997.
Yongwei Cao, Sela Mager, and Henry A. Lester Division of Biology, California Institute of Technology, Pasadena, California 91125
The rat serotonin transporter expressed in Xenopus oocytes 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 pKa 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.
Key words: protons; sodium; 5-HT; serotonin; SERT; Xenopus oocyte
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