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

Abstract

Functional 5-hydroxytryptamine type 3 (5-HT 3 ) 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 Å 3 enhanced submaximal 5-HTevoked current. Compounds larger than 110 Å 3 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 EC 50 . Sevoflurane and octanol inhibited 5-HT-evoked current at all 5-HT concentrations tested but had no effect upon the 5-HT EC 50 . Compared with previous data on homomeric h5-HT 3A receptors, the presence of the h5-HT 3B subunit reduces the enhancement of h5-HT 3 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.

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

“…Similarly, our previous work with 5-HT 3AB receptors using a submaximal (EC 10 ) concentration of 5-HT showed that at 2 MAC, chloroform (121%) induced more current enhancement than halothane (43%), whereas isoflurane induced no appreciable current enhancement (Stevens et al, 2005a). Consistent with those results, the present study using receptorsaturating concentrations of DA as agonist found that chloroform induced more channel gating enhancement than halothane, whereas isoflurane did not enhance gating.…”

“…Studies using a range of 5-HT concentrations demonstrate that for 5-HT 3A receptors, the presence of small, halogenated anesthetics significantly reduces the EC 50 for 5-HT without increasing the maximal response to 5-HT (Stevens et al, 2005b). However, this anesthetic-induced reduction in agonist EC 50 is greatly attenuated when 5-HT 3B subunits are incorporated to produce heteromeric 5-HT 3AB receptors (Stevens et al, 2005a). The present study sought to define the underlying mechanism accounting for the difference in anesthetic-induced sensitivity to agonist between the two 5-HT 3 receptor subtypes.…”

“…However, heteromeric 5-HT 3AB receptors have been found to be generally much less sensitive to such anestheticinduced potentiation of current responses than homomeric 5-HT 3A receptors (Stevens et al, 2005a). Studies using a range of 5-HT concentrations demonstrate that for 5-HT 3A receptors, the presence of small, halogenated anesthetics significantly reduces the EC 50 for 5-HT without increasing the maximal response to 5-HT (Stevens et al, 2005b).…”

Novel Activation of Voltage-gated K+ Channels by Sevoflurane

“…Relationship to Other Ion Channels-Resembling the pharmacological profile of K-Shaw2, the ionotropic 5-HT3 receptor also exhibits differential dual modulation by inhaled anesthetics (16,20,(42)(43). However, these anesthetics appear to interact with this receptor in a non-competitive manner and the anesthetic effect correlates with the molecular size of the drug used.…”

Involvement of 5-hydroxytryptamine type 3 receptors in sevoflurane-induced hypnotic and analgesic effects in mice

“…The 5-HT 3 receptors are widely distributed in both the central and peripheral nervous system and are involved in the physiologic and pathologic processes that mediate nausea, vomiting, peripheral nociception, and central antinociception [5,20]. Previous studies have shown that inhalation anesthetics modulate 5-HT 3 receptors [25,26]. Sevoflurane is a halogenated inhalation anesthetic.…”