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Influence of sodium substitutes on 5‐HT‐mediated effects at mouse 5‐HT 3 receptors
Author(s) -
Barann M,
Schmidt K,
Göthert M,
Urban B W,
Bönisch H
Publication year - 2004
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705788
Subject(s) - chemistry , tetramethylammonium , choline , methylamine , potency , sodium , 5 ht receptor , receptor , tris , biophysics , stereochemistry , serotonin , biochemistry , in vitro , ion , biology , organic chemistry
The influence of sodium ion substitutes on the 5‐hydroxytryptamine (5‐HT)‐induced flux of the organic cation [ 14 C]guanidinium through the ion channel of the mouse 5‐HT 3 receptor and on the competition of 5‐HT with the selective 5‐HT 3 receptor antagonist [ 3 H]GR 65630 was studied, unless stated otherwise, in mouse neuroblastoma N1E‐115 cells. Under physiological conditions (135 m M sodium), 5‐HT induced a concentration‐dependent [ 14 C]guanidinium influx with an EC 50 (1.3 μ M ) similar to that in electrophysiological studies. The stepwise replacement of sodium by increasing concentrations of the organic cation hydroxyethyl trimethylammonium (choline) concentration dependently caused both a rightward shift of the 5‐HT concentration–response curve and an increase in the maximum effect of 5‐HT. Complete replacement of sodium resulted in a 34‐fold lower potency of 5‐HT and an almost two times higher maximal response. A low potency of 5‐HT in choline buffer was also observed in other 5‐HT 3 receptor‐expressing rodent cell lines (NG 108‐15 or NCB 20). Replacement of Na + by Li + left the potency and maximal effects of 5‐HT almost unchanged. Replacement by tris (hydroxymethyl) methylamine (Tris), tetramethylammonium (TMA) or N ‐methyl‐ D ‐glucamine (NMDG) caused an increase in maximal response to 5‐HT similar to that caused by choline. The potency of 5‐HT was only slightly reduced by Tris, to a high degree decreased by TMA (comparable to the decrease by choline), but not influenced by NMDG. The potency of 5‐HT in inhibiting [ 3 H]GR65630 binding to intact cells was 35‐fold lower when sodium was completely replaced by choline, but remained unchanged after replacement by NMDG. The results are compatible with the suggestion that choline competes with 5‐HT for the 5‐HT 3 receptor; the increase in maximal response may be partly due to a choline‐mediated delay of the 5‐HT‐induced desensitization. For studies of 5‐HT‐evoked [ 14 C]guanidinium flux through 5‐HT 3 receptor channels, NMDG appears to be an ‘ideal’ sodium substituent since it increases the signal‐to‐noise ratio without interfering with 5‐HT binding.British Journal of Pharmacology (2004) 142 , 501–508. doi: 10.1038/sj.bjp.0705788