Small-conductance calcium-activated potassium currents in mouse hyperexcitable denervated skeletal muscle

1. Hyperexcitability in denervated skeletal muscle is associated with the e xpression of SK3, a small-conductance Ca2+ -activated K+ channel (SK channe l). SK currents were examined in dissociated fibres from flexor digitorum. brevis (FDB) muscle using the whole-cell patch clamp configuration. 2. Depolarization activated a K+-selective, apamin-sensitive and iberiotoxi n-insensitive current, detected as a tail current upon repolarization, in f ibres from denervated but not innervated muscle, Dialysis of the fibres wit h 20 midi EGTA in the patch pipette solution eliminated the tail current, c onsistent with this current reflecting Ca2+-activated SK channels expressed only in denervated muscle. 3. Activation of SK tail currents depended on the duration of the depolariz ing pulse, consistent with a rise in intracellular Ca due to release from t he sarcoplasmic reticulum (SR) and influx through voltage-gated Ca2+ channe ls. 4. The envelope of SK tail currents was diminished by 10 muM ryanodine for all pulse durations, whereas 2 mm cobalt reduced the SK tail current for pu lses greater than 80 ins, demonstrating that Ca2+ release from the SR durin g short pulses primarily activated SK channels. 5. In current clamp mode with the resting membrane potential set at -70 mV, denervation decreased the action potential threshold by similar to8 mV. Ap plication of apamin increased the action potential threshold in denervated fibres to that measured in innervated fibres, suggesting that SK channel ac tivity modulates the apparent action potential threshold. 6. These results are consistent with a model in which SK channel activity i n the T-tubules of denervated skeletal muscle causes a local increase in K concentration that results in hyperexcitability.