Inhibition by wortmannin of M‐current in bullfrog sympathetic neurones

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Abstract
1 The actions of wortmannin, an inhibitor of myosin light chain kinase (MLCK), on M-type potassium current of dissociated bullfrog sympathetic neurones have been examined. 2 The amplitude of M-current was measured by whole cell recordings from cells pretreated with wortmannin (0.01–10 μm) or the wortmannin vehicle, dimethylsulphoxide (0.0001–0.1 vol%), for 30 min. Internal (recording pipette) solutions having three different pCa values (6, 7 and 8) were used for the measurements. 3 Irrespective of the pCa, M-current was not detectable when the cells were pretreated with 10 μm wortmannin. Wortmannin, 3 μm, produced 85–95% inhibition of the M-current. Pretreatment with 10–30 nm wortmannin was without effect on M-current. 4 The M-current inhibition by wortmannin at concentrations of 0.1–1 μm depended on the pCa of the internal solution. Inhibition occurred only when the calcium-rich (pCa = 6) internal solution was used. 5 Pre-treatment of the cells with wortmannin (10 μm) did not affect rapidly-inactivating A-type or delayed rectifier-type potassium currents nor did it alter inwardly rectifying sodium-potassium current (IH). 6 These observations show that M-current inhibition by wortmannin has two pharmacological profiles. One is calcium-dependent and occurs at lower concentrations (0.1–1 μm), and is attributed to inhibition of MLCK by wortmannin. At higher concentrations (3–10 μm), wortmannin has an additional, calcium-independent action, inhibiting the M-current by an unknown mechanism.