Received for publication June 8, 2005.
Revised August 3, 2005.
Accepted for publication August 3, 2005.

General Anesthetic-induced Channel Gating Enhancement of 5-HT₃ Receptors is Dependent on Receptor Subunit Composition

Abstract

Serotonin (5-hydroxytryptamine) type 3 (5-HT₃) receptors are members of an anesthetic-sensitive superfamily of Cys-loop ligand-gated ion channels that can be formed as homomeric 5-HT_3A or heteromeric 5-HT_3AB receptors. When the efficacious agonist 5-HT is used, the inhaled anesthetics halothane and chloroform (at clinically relevant concentrations) significantly reduce the agonist EC₅₀ for 5-HT_3A receptors, but not for 5-HT_3AB receptors. In the present study we used dopamine (DA), a highly inefficacious agonist for 5-HT₃ receptors, to determine whether the difference in sensitivity between 5-HT_3A and 5-HT_3AB receptors to the potentiating effects of halothane and chloroform is due to differential modulation of agonist affinity, channel gating, or both. Using the two-electrode voltage-clamp technique with 5-HT_3A and 5-HT_3AB receptors expressed in Xenopus oocytes, we found that in a concentration-dependent fashion, chloroform and halothane enhanced currents evoked by receptor-saturating concentrations of DA for both receptor subtypes, but that the magnitude of enhancement was substantially greater for 5-HT_3A receptors than for 5-HT_3AB receptors. Isoflurane induced only a small enhancement of currents evoked by receptor-saturating concentrations of DA for 5-HT_3A receptors, and no enhancement for 5-HT_3AB receptors. For both receptor subtypes, none of the three test anesthetics significantly altered the agonist EC₅₀ for DA, implying that these anesthetics do not affect agonist binding affinity. Our results show that chloroform, halothane, and (to a much lesser degree) isoflurane enhance channel gating for 5-HT_3A receptors, and that the incorporation of 5-HT_3B subunits to produce heteromeric 5-HT_3AB receptors markedly attenuates the ability of these anesthetics to enhance channel gating.

Key words: 5-HT3 Receptor, Agonist binding affinity, Channel gating efficacy, General anesthetic, Ligand-gated ion channel, Partial agonist

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