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Volume 17, Number 10,
Issue of May 15, 1997
pp. 3401-3411
Copyright ©1997 Society for Neuroscience
Drosophila Serotonin Transporters Have
Voltage-Dependent Uptake Coupled to a Serotonin-Gated Ion Channel
Received Dec. 3, 1996; revised Jan. 31, 1997; accepted Feb. 22, 1997.
A. Galli,
C.I. Petersen,
M. deBlaquiere,
R.D. Blakely, and
L.J. DeFelice
Center for Molecular Neuroscience, Department of Pharmacology,
Vanderbilt University Medical Center, Nashville, Tennessee 37232-6600
Serotonin (5HT) transporters (SERTs) couple to existing ion
gradients to transport 5HT into presynaptic terminals. In mammalian SERTs, the transport cycle is reported as electroneutral, with a
translocation of zero net charge, and 5HT uptake is independent of
membrane voltage. Yet mammalian SERTs exhibit 5HT-induced currents, and
Drosophila SERTs (dSERTs) show voltage-dependent uptake.
Thus, the relationship between uptake and current remains
controversial; furthermore, the number of 5HT molecules translocated
per ion channel event is unknown. To investigate this, we have used
heterologous expression of cloned dSERTs to measure 5HT flux and dSERT
currents concurrently under voltage clamp, and we have used fluctuation analysis to measure the size of the elementary ionic events in the same
cells. RNA-injected Xenopus oocytes accumulate 5HT, and paroxetine or desipramine inhibit this uptake. RNA-injected oocytes also display paroxetine-sensitive 5HT-induced currents and
5HT-independent leak currents. Na replacement decreases the uptake and
the induced currents. 5HT-induced current and 5HT uptake both increase
at negative potentials, where 5HT carries ~5% of the induced
current. Recently, several groups have reported similar phenomena for
other transporters, in which transmitter-induced currents exceed the predictions of coupled transport. We now provide evidence that in
dSERT, ~500 5HT molecules are translocated per channel opening, which, at  20 mV, carries ~10,000 electronic charges. These data support a model in which 500 SERT cycles occur for each 5HT-induced channel opening or a model in which 500 5HT molecules and 10,000 electronic charges pass through a common pore.
Key words:
serotonin;
transporter;
uptake;
antidepressants;
channels;
Xenopus oocytes
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