Abstract

Maurotoxin, a 34-amino acid toxin from Scorpio maurusscorpion venom, was examined for its ability to inhibit cloned human SK (SK1, SK2, and SK3), IK1, and Slo1 calcium-activated potassium (K_Ca) channels. Maurotoxin was found to produce a potent inhibition of Ca²⁺-activated ⁸⁶Rb efflux (IC₅₀, 1.4 nM) and inwardly rectifying potassium currents (IC₅₀, 1 nM) in CHO cells stably expressing IK1. In contrast, maurotoxin produced no inhibition of SK1, SK2, and SK3 small-conductance or Slo1 large-conductance K_Ca channels at up to 1 μM in physiologically relevant ionic strength buffers. Maurotoxin did inhibit ⁸⁶Rb efflux (IC₅₀, 45 nM) through, and ¹²⁵I-apamin binding (K_i, 10 nM) to SK channels in low ionic strength buffers (i.e., 18 mM sodium, 250 mM sucrose), which is consistent with previous reports of inhibition of apamin binding to brain synaptosomes. Under similar low ionic strength conditions, the potency for maurotoxin inhibition of IK1 increased by ∼100-fold (IC₅₀, 14 pM). In agreement with its ability to inhibit recombinant IK1 potassium channels, maurotoxin was found to potently inhibit the Gardos channel in human red blood cells and to inhibit the K_Ca in activated human T lymphocytes without affecting the voltage-gated potassium current encoded by Kv1.3. Maurotoxin also did not inhibit Kv1.1 potassium channels but potently blocked Kv1.2 (IC₅₀, 0.1 nM). Mutation analysis indicates that similar amino acid residues contribute to the blocking activity of both IK1 and Kv1.2. The results from this study show that maurotoxin is a potent inhibitor of the IK1 subclass of K_Ca potassium channels and may serve as a useful tool for further defining the physiological role of this channel subtype.