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NEUROPHARMACOLOGY

General Anesthetic-Induced Channel Gating Enhancement of 5-Hydroxytryptamine Type 3 Receptors Depends on Receptor Subunit Composition

Department of Anesthesia and Critical Care, Massachusetts General Hospital, and Department of Anesthesia, Harvard Medical School, Boston, Massachusetts (K.S., P.A.D., D.E.R.); and Neuroscience Program, University of California at San Diego, San Diego, California (R.J.S.)

5-Hydroxytryptamine (serotonin) (5-HT) 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 chloroform and halothane enhanced currents evoked by receptor-saturating concentrations of DA for both receptor subtypes in a concentration-dependent manner 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.

Address correspondence to: Dr. Ken Solt, Department of Anesthesia and Critical Care, Massachusetts General Hospital, 55 Fruit St., Edwards 505, Boston, MA 02114. E-mail: ksolt{at}partners.org

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