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.
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1 June 2004
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May 17 2004
A Gastropod Toxin Selectively Slows Early Transitions in the Shaker K Channel's Activation Pathway
Jon T. Sack,
Jon T. Sack
1Hopkins Marine Station of Stanford University, Department of Biological Sciences, Pacific Grove, CA 93950
2Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305
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Richard W. Aldrich,
Richard W. Aldrich
2Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305
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William F. Gilly
William F. Gilly
1Hopkins Marine Station of Stanford University, Department of Biological Sciences, Pacific Grove, CA 93950
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Jon T. Sack
1Hopkins Marine Station of Stanford University, Department of Biological Sciences, Pacific Grove, CA 93950
2Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305
Richard W. Aldrich
2Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305
William F. Gilly
1Hopkins Marine Station of Stanford University, Department of Biological Sciences, Pacific Grove, CA 93950
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: [email protected]
Abbreviations used in this paper: BrMT, 6-bromo-2-mercaptotryptamine; HEPES, n-2-hydroxyethylpiperazine-n′-2-ethanesulfonic acid; ShBΔ, Shaker B(Δ6−46); NMG, n-methyl-d-glucamine; TCEP, tris-carboxyethylphosphine.
Received:
February 24 2004
Accepted:
April 12 2004
Online ISSN: 1540-7748
Print ISSN: 0022-1295
The Rockefeller University Press
2004
J Gen Physiol (2004) 123 (6): 685–696.
Article history
Received:
February 24 2004
Accepted:
April 12 2004
Citation
Jon T. Sack, Richard W. Aldrich, William F. Gilly; A Gastropod Toxin Selectively Slows Early Transitions in the Shaker K Channel's Activation Pathway . J Gen Physiol 1 June 2004; 123 (6): 685–696. doi: https://doi.org/10.1085/jgp.200409047
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