Novel mechanism of modulation at a ligand-gated ion channel; action of 5-Cl-indole at the 5-HT3 A receptor

Powell, Andrew D. and Grafton, Gillian and Roberts, Alexander and Larkin, Shannon and O'Neill, Nathanael and Palandri, Josephine and Otvos, Reka and Cooper, Alison J and Ulens, Chris and Barnes, Nicholas M (2016) Novel mechanism of modulation at a ligand-gated ion channel; action of 5-Cl-indole at the 5-HT3 A receptor. British Journal of Pharmacology, 173 (24). pp. 3467-3479. ISSN 0007-1188

Powell et al BJP (2016).pdf - Accepted Version

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Background and purpose
The 5-HT3 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-HT3A 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-HT3 receptor was assessed using single cell electrophysiological recordings and [3H]granisetron binding with HEK293 cells stably expressing the 5-HT3 receptor.
Key results
Cl-indole failed to evoke 5-HT3A receptor mediated responses (up to 30 µM) or display affinity for the [3H]granisetron binding site. However, in the presence of Cl-indole, termination of 5-HT application revealed tail currents mediated via the 5-HT3A receptor that were independent of the preceding 5-HT concentration but were antagonised by the 5-HT3 receptor antagonist, ondansetron. These tail currents were absent in the 5-HT3AB 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 h5-HT3A 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.

Item Type: Article
Identification Number:
16 September 2016Accepted
1 November 2016Published Online
Subjects: CAH01 - medicine and dentistry > CAH01-01 - medicine and dentistry > CAH01-01-01 - medical sciences (non-specific)
CAH02 - subjects allied to medicine > CAH02-05 - medical sciences > CAH02-05-04 - anatomy, physiology and pathology
CAH02 - subjects allied to medicine > CAH02-02 - pharmacology, toxicology and pharmacy > CAH02-02-01 - pharmacology
Divisions: Faculty of Health, Education and Life Sciences > School of Health Sciences
Depositing User: Andy Powell
Date Deposited: 22 May 2017 08:47
Last Modified: 12 Jan 2022 11:19

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