Direct interaction of serotonin type 3 receptor ligands with recombinant and native α9α10-containing nicotinic cholinergic receptors

Abstract

In the present work, we characterized the effects of serotonin type 3 receptor ligands on recombinant and native α9α10-containing nicotinic acetylcholine receptors (nAChRs). Our results indicate that the recombinant α9α10 nAChR shares striking pharmacological properties with 5-HT3 ligand-gated ion channels. Thus, 5-HT3 receptor antagonists block ACh-evoked currents in α9α10-injected Xenopus laevis oocytes with a rank order of potency of tropisetron (IC50, 70.1 ± 0.9 nM) > ondansetron (IC50, 0.6 ± 0.1 μM) = MDL 72222 (IC50, 0.7 ± 0.1 μM). Although serotonin does not elicit responses in α9α10-injected oocytes, it blocks recombinant α9α10 receptors in a noncompetitive and voltage-dependent manner (IC50, 5.4 ± 0.6 μM). On the other hand, we demonstrate an in vivo correlate of these properties of the recombinant receptor, with those of the α9α10-containing nAChR of frog saccular hair cells. The possibility that the biogenic amine serotonin might act as a neuromodulator of the cholinergic efferent transmission in the vestibular apparatus and in the organ of Corti is discussed.