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Evidence for noncompetitive modulation of substrate‐induced serotonin release
Author(s) -
Rothman Richard B.,
Baumann Michael H.,
Blough Bruce E.,
Jacobson Arthur E.,
Rice Kenner C.,
Partilla John S.
Publication year - 2010
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.20804
Subject(s) - serotonin transporter , fenfluramine , serotonin , non competitive inhibition , chemistry , pharmacology , transporter , reuptake inhibitor , substrate (aquarium) , endocrinology , medicine , biochemistry , enzyme , biology , receptor , ecology , gene
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. Synapse 64:862–869, 2010. © 2010 Wiley‐Liss, Inc.