Alcohol modulation of neuronal nicotinic acetylcholine receptors is alpha subunit dependent.
BACKGROUND
We have previously shown that n-alcohols exert a dual action on the alpha4beta2-type neuronal nicotinic acetylcholine (ACh) receptors (AChRs), with shorter-chain alcohols potentiating and longer-chain alcohols inhibiting ACh-induced currents. Ethanol potentiates the current in alpha4beta2 receptors, yet it has little or no effect on the alpha3beta2 receptors. Because the alpha4 AChRs are present predominantly in the brain, whereas the alpha3 AChRs are present predominantly in the peripheral ganglia, the differential action of ethanol on the alpha4beta2 and alpha3beta2 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 alpha3-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 alpha3beta2 AChRs recombinantly expressed in human embryonic kidney tsA201 cells by using the whole-cell patch clamp technique.


RESULTS
The ACh-induced currents in the alpha3beta2 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 alpha3beta2 AChR compared with the alpha4beta2 AChR. This explains why ethanol, which was at the transition point, has little or no effect on the alpha3beta2 AChR.


CONCLUSIONS
The alpha3beta2 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 alpha4beta2 and alpha3beta2 AChRs may explain the differential action of ethanol on the central nervous system.
Zuo
Yi
Y
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Kuryatov
Alexander
A
Lindstrom
Jon M
JM
Yeh
Jay Z
JZ
Narahashi
Toshio
T
D000438:Alcohols / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D011978:Receptors, Nicotinic / Q000378:metabolism / Q000502:physiology*
D000438:Alcohols; D011978:Receptors, Nicotinic; C419362:nicotinic receptor alpha3beta2; C403531:nicotinic receptor alpha4beta2; D000431:Ethanol