Alcohol Modulation of Neuronal Nicotinic Acetylcholine Receptors Is Subunit Dependent

Background: We have previously shown that n-alcohols exert a dual action on the 4 2-type neuronal nicotinic acetylcholine (ACh) receptors (AChRs), with shorter-chain alcohols potentiating and longerchain alcohols inhibiting ACh-induced currents. Ethanol potentiates the current in 4 2 receptors, yet it has little or no effect on the 3 2 receptors. Because the 4 AChRs are present predominantly in the brain, whereas the 3 AChRs are present predominantly in the peripheral ganglia, the differential action of ethanol on the 4 2 and 3 2 AChRs may contribute to its differential effects on the brain and the peripheral nervous system. The purpose of this study was to characterize the actions of alcohols on an 3-containing nicotinic receptor and to further understand the mechanism underlying the differential action of ethanol on the two receptor subtypes. Methods: ACh-induced currents were recorded from human 3 2 AChRs recombinantly expressed in human embryonic kidney tsA201 cells by using the whole-cell patch clamp technique. Results: The ACh-induced currents in the 3 2 receptors were potentiated by methanol and inhibited by longer-chain alcohols. The transition point from potentiation to inhibition and the cutoff point were both shifted to shorter alcohols in the 3 2 AChR compared with the 4 2 AChR. This explains why ethanol, which was at the transition point, has little or no effect on the 3 2 AChR. Conclusions: The 3 2 AChRs are insensitive to ethanol because ethanol is at the transition point from potentiation to inhibition among n-alcohols with different carbon-chain lengths. The differential action on the 4 2 and 3 2 AChRs may explain the differential action of ethanol on the central nervous system.