H441 cells express an amiloride-sensitive Na⁺ conductance (G_Na) similar to that associated with co-expression of the epithelial Na⁺ channel (ENaC) α, β and γ subunits, and regulated increases in G_Na seem to underlie the cAMP-evoked stimulation of Na⁺ transport seen in these cells (Clunes et al., 2004). However, as well as increasing [Ca²⁺]_i, thapsigargin (1 μM) also increases the short circuit current recorded from these cells (ΔI_SC = 24.3 ± 2.4 μA cm², n = 6, P < 0.01), suggesting that Na⁺ transport is also controlled via [Ca²⁺]_i. This was unexpected as Ca²⁺ is thought to inhibit ENaC (Ishikawa et al., 1998) and so, to establish the physiological basis of this response, we explored the effects of thapsigargin (1 μM) upon the membrane currents recorded from groups of 2-5 cells (Clunes et al., 2004). Thapsigargin consistently evoked Ca²⁺-dependent membrane currents (Fig 1A) and the current recorded from thapsigargin-treated cells reversed at a potential close to E_K (Fig 1B). This Ca²⁺-mobilising agent had thus increased G_K and further analysis showed that this was associated with a hyperpolarization of V_m (control: -50 ± 6 mV; thapsigargin: -78 ± 1 mV, P < 0.01). We also studied the effects of thapsigargin upon G_Na by characterising amiloride-sensitive currents in cells treated with clotrimazole (1 μM) which was shown to block the thapsigargin-evoked increase in G_K (Clunes et al., 2005). These experiments confirmed the expression of a selective Na⁺ conductance and showed that the magnitude of this conductance increased slightly during exposure to thapsigargin (control: 157 ± 16 pS cell^-1; thapsigargin: 267 ± 24 pS cell^-1, n = 7, P < 0.02) a result that contrasts with earlier work (Ishikawa et al., 1998). Thapsigargin may thus stimulate Na⁺ transport by (i) hyperpolarising V_m and increasing the driving force for Na⁺ entry and (ii) increasing G_Na by an unknown mechanism.