Human neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes predict efficacy of halogenated compounds that disobey the Meyer-Overton rule.
BACKGROUND
According to the Meyer-Overton rule, anesthetic potency of a substance can be predicted by its lipid solubility, but a group of halogenated volatile compounds predicted to induce anesthesia does not obey this rule. Thus, these compounds are useful tools for studies of molecular targets of anesthetics. Human neuronal nicotinic acetylcholine receptor (hnAChR) subunits have been recently cloned, which allowed the authors to assess whether these receptors could differentiate among volatile anesthetic and nonimmobilizer compounds. This study provides the first data regarding anesthetic sensitivity of hnAChRs.


METHODS
alpha2beta4, alpha3beta4, and alphaabeta2 hnAChRs were expressed in Xenopus oocytes, and effects of volatile anesthetics isoflurane and F3 (1-chioro-1,2,2-triflurocyclobutane, 1A) and nonimmobilizers F6 (1,2-dichlorohexafluorocyclobutane, 2N) and F8 (2,3-dichlorooctafluorobutane) on the peak acetylcholine-gated currents were studied using the two-electrode voltage-clamp technique.


RESULTS
Isoflurane and F3 inhibited all the hnAChRs tested in a concentration-dependent manner. Isoflurane at a concentration corresponding to 1 minimum alveolar concentration (MAC) inhibited 83, 69, and 71% of ACh-induced currents in alpha2beta4, alpha3beta4, and alpha4beta2 hnAChRs, respectively, and 1 MAC of F3 inhibited 64, 44, and 61% of currents gated in those receptors. F6 (8-34 microM) did not cause any changes in currents gated by any of the receptors tested. F8 (4-18 microM) did not alter the currents gated in either alpha3beta4 or alpha4beta2 receptors, but caused a small potentiation of alpha2beta4 hnAChRs without a concentration-response relation.


CONCLUSIONS
The in vivo potency and effectiveness of volatile anesthetic and nonimmobilizer compounds were consistent with their actions on hnAChRs expressed in a recombinant expression system, suggesting a potential participation of these receptors in the mechanisms of anesthesia.
Cardoso
R A
RA
Institute for Cellular and Molecular Biology, University of Texas, Austin 78712-1095, USA.
Yamakura
T
T
Brozowski
S J
SJ
Chavez-Noriega
L E
LE
Harris
R A
RA
D000109:Acetylcholine / Q000494:pharmacology; D018685:Anesthetics, Inhalation / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002999:Clone Cells; D005260:Female; D006801:Humans; D006843:Hydrocarbons, Chlorinated / Q000737:chemistry / Q000494:pharmacology*; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry / Q000494:pharmacology*; D008055:Lipids; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009865:Oocytes; D018408:Patch-Clamp Techniques; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
D018685:Anesthetics, Inhalation; D006843:Hydrocarbons, Chlorinated; D006845:Hydrocarbons, Fluorinated; D008055:Lipids; D011978:Receptors, Nicotinic; D000109:Acetylcholine