Distal airway epithelia absorb Na⁺ from the airway surface liquid and this process is acutely regulated by cAMP-dependent agonists (Olver et al. 2004). However, some groups attribute this response to an increase in sodium conductance (G_Na,see e.g. Collett et al. 2002) whilst others suggest that such agonists act by hyperpolarizing V _m and thus increasing the driving force for Na⁺ entry (O′Grady et al. 2000). Here we report the effects of cAMP on the Na⁺ conductance expressed by dexamethasone-stimulated H441 distal airway epithelial cells (Clunes et al. 2004), which has properties essentially identical to the conductance associated with co-expression of α, β and γ-ENaC (Canessa et al. 1994).Exposing the cells to a cocktail of cAMP-activating drugs caused a clear increase in G_Na (Fig 1A,C) whilst no such change in Goccurred Na in control cells (Fig 1B,C). The cAMP-activating drugs had no effect upon the reversal potential for the amiloride-sensitive component of the membrane current (control E _rev 74 ± 11 cf. cAMP-stimulated E 82 ± 8 mV), and so this increase in conductance occurs with no change in Na⁺ selectivity. In contrast, the cAMP cocktail caused a depolarising shift in the reversal potential for the total membrane current (P<0.05, ∆E _rev 18 ± 4 mV) indicating the response is associated with a depolarisation of Vm.These data thus suggest that cAMP-stimulated Na⁺ absorption reflects an increase in the activity and or surface abundance of highly selective sodium channels. Figure 1. H441 cells were grown (~24 h) on glass coverslips in the presence of 200 nM dexamethasone before being studied using the perforated patch technique; all data are mean ± S.E.M. (n>4). The current − voltage relationship for the amiloride-sensitive current (I_Amil) measured at 0 and 20 min in control (A) or cAMP stimulated cells (B, 10 µM forskolin, 100 µM isobutylmethylxanthine, 1 mM N6,2′-O-dibutyryladenonsine 3′5′-cyclic monophoshate). C, Estimates of the amiloride-sensitive membrane conductance (G_Amil) from linear regression of data collected at negative holding potentials at 0 and 20 min. * denotes significance P<0.05 (Student’s t test).