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¹ Hopkins Marine Station of Stanford University, Department of Biological Sciences, Pacific Grove, CA 93950
² Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305

Address correspondence to William F. Gilly, Hopkins Marine Station of Stanford University, 120 Ocean View Boulevard, Pacific Grove, CA 93950. Fax: (831) 375-0793; email: lignje{at}stanford.edu

A toxin from a marine gastropod's defensive mucus, a disulfide-linked dimer of 6-bromo-2-mercaptotryptamine (BrMT), was found to inhibit voltage-gated potassium channels by a novel mechanism. Voltage-clamp experiments with Shaker K channels reveal that externally applied BrMT slows channel opening but not closing. BrMT slows K channel activation in a graded fashion: channels activate progressively slower as the concentration of BrMT is increased. Analysis of single-channel activity indicates that once a channel opens, the unitary conductance and bursting behavior are essentially normal in BrMT. Paralleling its effects against channel opening, BrMT greatly slows the kinetics of ON, but not OFF, gating currents. BrMT was found to slow early activation transitions but not the final opening transition of the Shaker ILT mutant, and can be used to pharmacologically distinguish early from late gating steps. This novel toxin thus inhibits activation of Shaker K channels by specifically slowing early movement of their voltage sensors, thereby hindering channel opening. A model of BrMT action is developed that suggests BrMT rapidly binds to and stabilizes resting channel conformations.

Key Words: Shaker • Kv • gating • potassium channel • neurotoxin

Abbreviations used in this paper: BrMT, 6-bromo-2-mercaptotryptamine; HEPES, N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid; ShB, Shaker B(6–46); NMG, N-methyl-D-glucamine; TCEP, tris-carboxyethylphosphine.

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