Renal inner medullary collecting duct cells (mIMCD-3) possess a Cl^– conductance (CaCC) regulated by intracellular Ca²⁺ via Ca²⁺ influx across the apical plasma membrane (Stewart et al, 2001). Tpc1 is a Ca²⁺ permeable channel activated by depolarisation which is expressed in mIMCD-3 cells (Sayer et al, 2006) but whose physiological role is undefined. Here we investigate the effect of membrane depolarisation on CaCC in mIMCD-3 cells. Membrane conductance of cells on coverslips was measured using the slow whole cell patch-clamp technique. Data are given as mean ± SEM (n), difference between mean values was determined by Student’s t test. When the membrane potential was held at -60mV (V_hold) with brief excursions to +60mV, only a small basal K⁺ conductance was detected. In contrast, when V_hold was 0mV with brief excursions to ±60mV, there was a slow increase in conductance following a delay of ~60s. Whole cell conductance increased from 30.7 ± 3 & -18.4 ± 2pA/pF (at V_hold = -60mV) to 214.4 ± 22 & -108.9 ± 9pA/pF (at V_hold = 0mV) (n = 37) reaching a plateau after ~15mins (T_0.5 = 472 ± 23s). Currents were outwardly-rectifying, time-independent and Cl^– selective. Repolarisation (V_hold = –60mV), reversed the conductance increase to control values (T_0.5 = 90 ± 10s, n=15). The sensitivity to depolarisation and dependence on Ca²⁺ influx suggests the involvement of a tpc1 like channel in CaCC activation. A distinguishing feature of tpc1 is its Al³⁺ sensitivity (Kawano et al, 2004). Whereas 1mM Al³⁺ did not effect basal conductance at –60mV, the activation of CaCC was abolished by 1mM Al³⁺ when V_hold was 0mV. The effect of 1mM Al³⁺ was completely reversible on washout of Al³⁺ with V_hold at 0mV but subsequent activation of CaCC was ~four fold faster. Finally, 1mM Al³⁺ failed to inhibit the pre-activated Cl^– conductance at 0mV. Taken together these data indicate that Al³⁺ blocks the depolarisation-induced activation of CaCC, but Al³⁺ has no direct blocking effect on the activated Cl^– conductance itself. This suggests that the physiological role of tpc1 is to act as the voltage-sensor upon membrane depolarisation to regulate CaCC in the apical membrane of IMCD cells.