Evidence for noncompetitive modulation of substrate-induced serotonin release.

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Rothman RB, Baumann MH, Blough BE, Jacobson AE, Rice KC, Partilla JS

Evidence for noncompetitive modulation of substrate-induced serotonin release.

Synapse. 2010 Nov;64(11):862-9. doi: 10.1002/syn.20804.

PubMed ID

20842720 [ View in PubMed

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Abstract

Prior work indicated that serotonin transporter (SERT) inhibitors competitively inhibit substrate-induced [(3)H]5-HT release, producing rightward shifts in the substrate-dose response curve and increasing the EC(50) value without altering the E(max). We hypothesized that this finding would not generalize across a number of SERT inhibitors and substrates, and that the functional dissociation constant (Ke) of a given SERT inhibitor would not be the same for all tested substrates. To test this hypothesis, we utilized a well-characterized [(3)H]5-HT release assay that measures the ability of a SERT substrate to release preloaded [(3)H]5-HT from rat brain synaptosomes. Dose-response curves were generated for six substrates (PAL-287 [naphthylisopropylamine], (+)-fenfluramine, (+)-norfenfluramine, mCPP [meta-chlorophenylpiperazine], (+/-)-MDMA, 5-HT) in the absence and presence of a fixed concentration of three SERT inhibitors (indatraline, BW723C86, EG-1-149 [4-(2-(benzhydryloxy)ethyl)-1-(4-bromobenzyl)piperidine oxalate]). Consistent with simple competitive inhibition, all SERT inhibitors increased the EC(50) value of all substrates. However, in many cases a SERT inhibitor decreased the E(max) value as well, indicating that in the presence of the SERT inhibitor the substrate became a partial releaser. Moreover, the Ke values of a given SERT inhibitor differed among the six SERT substrates, indicating that each inhibitor/substrate combination had a unique interaction with the transporter. Viewed collectively, these findings suggest that it may be possible to design SERT inhibitors that differentially regulate SERT function.

DrugBank Data that Cites this Article

Drugs

Fenfluramine

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Fenfluramine	Sodium-dependent serotonin transporter	Protein	Humans	Yes	Substrate Inhibitor	Details