Alpha4beta2 Neuronal Nicotinic Acetylcholine Receptors in the Central Nervous System Are Inhibited by Isoflurane and Propofol, but alpha7-type Nicotinic Acetylcholine Receptors Are Unaffected

Abstract

The mechanisms of action of general anesthetics are not completely understood. Many general anesthetics are reported to potentiate gamma-aminobutyric acid (GABAA) and glycine receptors in the central nervous system (CNS) and to inhibit the muscle-type nicotinic acetylcholine receptor (nAChR). The effects of general anesthetics on another family of ligand-gated ion channel in the CNS, the nAChRs, have not been defined. Two types of CNS acetylcholine receptor, the alpha4beta2 receptor or the alpha7 homomeric receptor, were expressed heterologously in Xenopus laevis oocytes. Using the standard two-microelectrode voltage-clamp technique, peak acetylcholine-gated current was measured before and after coapplication of isoflurane or propofol. Coapplication of either isoflurane or propofol with acetylcholine resulted in potent, dose-dependent inhibition of the alpha4beta2 receptor current with median inhibitory concentrations of 85 and 19 micro Meter, respectively. The inhibition of the alpha4beta2 receptor by both isoflurane and propofol appears to be competitive with respect to acetylcholine. The alpha7 receptor current was not effected by either anesthetic. The CNS-type nAChRs are differentially affected by isoflurane and propofol. The alpha4beta2 receptor is affected by isoflurane more potently than the most sensitive GABAA or glycine receptor that has been reported, whereas the alpha7 homomeric receptor is not affected by either anesthetic. Inhibition of specific subtypes of nAChRs in the CNS, along with potentiation of GABAA and glycine receptors, may contribute to the effects and side effects of general anesthetics.