Dual action of n-alcohols on neuronal nicotinic acetylcholine receptors

Yi Zuo, Gary L. Aistrup, William Marszalec, Alison Gillespie, Laura E. Chavez-Noriega, Jay Z. Yeh, Toshio Narahashi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

Alcohol is known to modulate the activity of a variety of neuroreceptors and ion channels. Recently, neuronal nicotinic acetylcholine receptors (nnAChRs) have become a specific focus of study because not only are they potently modulated by alcohol but also they regulate the release of various transmitters, including γ-aminobutyric acid (GABA) and dopamine, which play an important role in the behavioral effects of ethanol. Whereas the potency of normal alcohols (n-alcohols) to potentiate GABAA receptors and to inhibit N-methyl-D-aspartate receptors increases with carbon chain length, we have found that n-alcohols, depending on the carbon chain length, exert a dual action, potentiation and inhibition, on nnAChRs in primary cultured rat cortical neurons. The mechanism of dual action of n-alcohols on nnAChRs was further analyzed using human embryonic kidney cells expressing the α4β2 subunits. Shorter chain alcohols from methanol to n-propanol potentiated acetylcholine (ACh)-induced currents, whereas longer chain alcohols from n-pentanol to n-dodecanol inhibited the currents. n-Butanol either potentiated or inhibited the currents depending on the concentrations of ACh and butanol. The parameters for both potentiation (log EC200) and inhibition (log IC50) were linearly related to carbon number, albeit with different slopes. The slope for potentiation was -0.299, indicating a change in free energy change (ΔΔG) of 405 cal/mol/methylene group, whereas the slope for inhibition was -0.584, indicating a ΔΔG of 792 cal/mol. These results suggest that potentiating and inhibitory actions are exerted through two different binding sites. Ethanol decreased the potency of n-octanol to inhibit ACh currents, possibly resulting from an allosteric mechanism.

Original languageEnglish (US)
Pages (from-to)700-711
Number of pages12
JournalMolecular pharmacology
Volume60
Issue number4
StatePublished - 2001

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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