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The Journal of Neuroscience, June 15, 1999, 19(12):4705-4717
Transmembrane Domain I Contributes to the Permeation Pathway for
Serotonin and Ions in the Serotonin Transporter
Eric L.
Barker,
Kimberly R.
Moore,
Fariborz
Rakhshan, and
Randy D.
Blakely
Department of Pharmacology and Center for Molecular Neuroscience,
Vanderbilt University School of Medicine, Nashville, Tennessee
37232-6600
Mutation of a conserved Asp (D98) in the rat serotonin (5HT)
transporter (rSERT) to Glu (D98E) led to decreased 5HT transport capacity, diminished coupling to extracellular Na+
and Cl , and a selective loss of antagonist
potencies (cocaine, imipramine, and citalopram but not paroxetine or
mazindol) with no change in 5HT Km value.
D98E, which extends the acidic side chain by one carbon, affected the
rank-order potency of substrate analogs for inhibition of 5HT
transport, selectively increasing the potency of two analogs with
shorter alkylamine side chains, gramine, and dihydroxybenzylamine. D98E
also increased the efficacy of gramine relative to 5HT for inducing
substrate-activated currents in Xenopus laevis oocytes,
but these currents were noticeably dependent on extracellular medium
acidification. I-V profiles for substrate-independent and -dependent currents indicated that the mutation selectively impacts
ion permeation coupled to 5HT occupancy. The ability of the D98E mutant
to modulate selective aspects of substrate recognition, to perturb ion
dependence as well as modify substrate-induced currents, suggests that
transmembrane domain I plays a critical role in defining the permeation
pathway of biogenic amine transporters.
Key words:
serotonin; monoamine; transporter; biological transport; carrier proteins; molecular structure; permeation channel; selectivity
filter
Copyright © 1999 Society for Neuroscience 0270-6474/99/19124705-13$05.00/0
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