The 5-HT3 receptor is a ligand-gated ion channel that mediates for example fast synaptic neurotransmission in the CNS and PNS. 5-HT3 receptor antagonists are established anti-emetics in the clinic, they also offer symptomatic relief for patients with irritable bowel syndrome, yet, sometimes serious side-effects limits their use in this indication. The 5-HT3 receptor is modulated allosterically by various compounds including colchicine, alcohols and volatile anaesthetics but as yet, these modulators either lack potency or selectivity, which hinders investigation.
The present study reports a novel 5-HT3 receptor allosteric modulator that displays relatively high potency and selectivity; 5-chloro-indole (Cl-indole). Cl-indole potentiated 5-HT3 receptor mediated responses arising from heterologous expression of the h5-HT3A receptor (assessed by the affinity shift of agonists to compete for the radioligand binding site and by the increase in agonist action upon the h5-HT3A receptor-mediated increase in [Ca2+]i; the latter action was evident with a range of agonists with very low intrinsic activity to full agonists). Cl-indole was also able to modulate allosterically the mouse native 5-HT3 receptor.
Additional studies provided further support for the role of the C-terminus of the h5-HT3A subunit to promote stability of the arising 5-HT3 receptor complex and that ligand interaction with the 5-HT3A receptor impacted cell surface expression.
In summary, the study reports the identification of Cl-indole as a positive allosteric modulator of the 5-HT3 receptor along with extensions to our knowledge concerning a structural component of the 5-HT3A subunit that promotes stability and the trafficking of the subunit into the cell membrane. These studies increase our understanding of the 5-HT3 receptor, which may contribute to the design of better drugs targeting this receptor for therapeutic benefit
