The magnocellular neurosecretory cells of the hypothalamus (MNCs) regulate their electrical behaviour as a function of external osmolality through changes in the activity of osmosensitive ion channels. We now present evidence that the MNCs express an osmosensitive voltage-gated K(+) current (the OKC). Whole-cell patch-clamp experiments on acutely isolated MNCs were used to show that increases in the external osmolality from 295 to 325 mosmol/kg cause an increase in a slow, tetraethylammonium-insensitive outward current. The equilibrium potential for this current is close to the predicted E(K) in two different concentrations of external K(+). The OKC is sensitive to block by Ba(2+) (0.3 mm), and by the M-type K(+) current blockers linopirdine (150 microm) and XE991 (5 microm), and to enhancement by retigabine (10 microm), which increases opening of M-type K(+) channels. The OKC is suppressed by muscarine (30 microm) and is decreased by the L-type Ca(2+) channel blocker nifedipine (10 microm), but not by apamin (100 nm), which blocks SK-type Ca(2+)-dependent K(+) currents. Reverse transcriptase-polymerase chain reaction and immunocytochemical data suggest that MNCs express several members of the K(V)7 (KCNQ) family of K(+) channels, including K(V)7.2, 7.3, 7.4 and 7.5. Extracellular recordings of individual MNCs in a hypothalamic explant preparation demonstrated that an XE991- and retigabine-sensitive current contribute to the regulation of MNC firing. Our data suggest that the MNCs express an osmosensitive K(+) current that could contribute to the regulation of MNC firing by external osmolality and that could be mediated by K(V)7/M-type K(+) channels.