Isoform-specific enhancement of adenylyl cyclase activity by n-alkanols

Numerous studies suggest that cAMP signaling pathways play important roles in the development of and predisposition to alcoholism. Our previous study showed that cAMP generation by various isoforms of adenylyl cyclase (AC) exhibits a broad spectrum of responses to ethanol in the human embryonic kidney (HEK) 293 cell system overexpressing individual AC isoforms. These findings suggest that the target of ethanol's action in the cAMP-generating system is AC. However, it is unknown if the action of ethanol is direct or indirect.

The effect of a series of n-alkanols (ethanol to decanol) on dopamine (DA)-stimulated activity of AC isoforms type 6, 7, and 9 (AC6, AC7, and AC9) were examined in transfected HEK293 cells by cAMP accumulation assay.

n-Alkanols increased DA-stimulated cAMP production in an AC isoform-specific manner, and displayed the alcohol cutoff phenomenon (defined as the carbon chain length beyond which there is no further increase in the potency of an ascending series of n-alkanols). The n-alkanol cutoffs for AC6, AC7, and AC9 are butanol (C4), pentanol (C5), and equal to or greater than decanol (C10), respectively.

The results clearly indicate that, in the HEK293 expression system, the alcohol cutoff effect for n-alkanol potentiation of DA-stimulated AC activity is AC isoform specific. These results strongly suggest that alcohols interact directly with AC molecules.