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NEUROPHARMACOLOGY

Modulation of Human 5-Hydroxytryptamine Type 3AB Receptors by Volatile Anesthetics and n-Alcohols

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

Functional 5-hydroxytryptamine type 3 (5-HT₃) receptors can be formed by 5-HT_3A subunits alone or in combination with the 5-HT_3B subunit, but only the 5-HT_3A receptor has been previously studied with respect to the modulation by volatile anesthetics and n-alcohols. Using two-electrode voltage-clamp, we show for the first time the modulation of heteromeric human (h)5-HT_3AB receptors, expressed in Xenopus oocytes, by a series of n-alcohols and halogenated volatile anesthetics. At twice their anesthetic concentration, compounds having a molecular volume of less than 110 ų enhanced submaximal 5-HT-evoked current. Compounds larger than 110 ų inhibited submaximal 5-HT-evoked current. In experiments examining 5-HT concentration-response relationships, chloroform and butanol caused a slight decrease in the 5-HT EC₅₀. Sevoflurane and octanol inhibited 5-HT-evoked current at all 5-HT concentrations tested but had no effect upon the 5-HT EC₅₀. Compared with previous data on homomeric h5-HT_3A receptors, the presence of the h5-HT_3B subunit reduces the enhancement of h5-HT₃ receptors by smaller halogenated volatile anesthetics and n-alcohols. In summary, these results suggest that heteromeric h5-HT_3AB receptors are modulated by halogenated volatile anesthetics at clinically relevant concentrations, in addition to n-alcohols, suggesting that these receptors may be another physiological target for these compounds. The modulation is dependent upon the molecular volume of the compound, further supporting the concept of an anesthetic binding pocket of limited volume common on other Cys-loop ligand-gated ion channels. Incorporation of the 5-HT_3B subunit alters either the anesthetic binding site or the allosteric interactions between anesthetic binding and channel opening.

Address correspondence to: Dr. Paul A. Davies, Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Clinics 3, 55 Fruit Street, Boston, MA 02114-2696. E-mail: pdavies2{at}partners.org

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