Abstract | IKSO is a standing-outward potassium current found in cerebellar granule neurons which is inhibited by the activation of muscarinic M3 receptors. However the pathway between muscarinic receptor activation and current inhibition is unknown. Using two structurally distinct inhibitors of the activation of MEK1 (mitogen activated protein (MAP) kinase kinase 1), PD 98059 and U 0126, we have shown that the MAP kinase signalling cascade does not appear to underlie muscarinic inhibition of IKSO, recorded using whole-cell patch-clamp methods. Nevertheless, both PD 98059 and U 0126 caused an inhibition of IKSO when applied acutely with 30 μM of each compound producing around 50% inhibition of the current. In addition, U 0125, which is structurally related to U 0126 but has a much lower potency for inhibiting MEK1 activation, was also able to inhibit IKSO to a similar degree. Neither the inhibition by PD 98059 nor that by U 0126 was found to be voltage dependent. This was true whether the IKSO current was outward or inward. Block of IKSO by these two compounds may compromise interpretation of studies in intact neuronal preparations when they are used as MEK1 inhibitors. |
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