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Novel mechanism of modulation at a ligand‐gated ion channel; action of 5‐Cl‐indole at the 5‐HT 3 A receptor
Author(s) -
Powell Andrew D,
Grafton Gillian,
Roberts Alexander,
Larkin Shan,
O'Neill Nathanael,
Palandri Josephine,
Otvos Reka,
Cooper Alison J,
Ulens Chris,
Barnes Nicholas M
Publication year - 2016
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 - 10.1111/bph.13638
Subject(s) - allosteric regulation , agonist , allosteric modulator , indole test , receptor , chemistry , ion channel , mechanism of action , biophysics , 5 ht receptor , 5 ht3 receptor , ligand gated ion channel , pharmacology , stereochemistry , biochemistry , serotonin , biology , in vitro
Background and Purpose The 5‐HT 3 receptor is a prototypical member of the Cys‐loop ligand‐gated ion channel (LGIC) superfamily and an established therapeutic target. In addition to activation via the orthosteric site, receptor function can be modulated by allosteric ligands. We have investigated the pharmacological action of Cl‐indole upon the 5‐HT 3 A receptor and identified that this positive allosteric modulator possesses a novel mechanism of action for LGICs. Experimental Approach The impact of Cl‐indole upon the 5‐HT 3 receptor was assessed using single cell electrophysiological recordings and [ 3 H]‐granisetron binding in HEK293 cells stably expressing the 5‐HT 3 receptor. Key Results Cl‐indole failed to evoke 5‐HT 3 A receptor‐mediated responses (up to 30 μM) or display affinity for the [ 3 H]‐granisetron binding site. However, in the presence of Cl‐indole, termination of 5‐HT application revealed tail currents mediated via the 5‐HT 3 A receptor that were independent of the preceding 5‐HT concentration but were antagonized by the 5‐HT 3 receptor antagonist, ondansetron. These tail currents were absent in the 5‐HT 3 AB receptor. Furthermore, the presence of 5‐HT revealed a concentration‐dependent increase in the affinity of Cl‐indole for the orthosteric binding site of the human 5‐HT 3 A receptor. Conclusions and Implications Cl‐indole acts as both an orthosteric agonist and an allosteric modulator, but the presence of an orthosteric agonist (e.g. 5‐HT) is a prerequisite to reveal both actions. Precedent for ago‐allosteric action is available, yet the essential additional presence of an orthosteric agonist is now reported for the first time. This widening of the pharmacological mechanisms to modulate LGICs may offer further therapeutic opportunities.