Modulation of Kv3 subfamily potassium currents by the sea anemone toxin BDS: significance for CNS and biophysical studies

Shuk Yin M Yeung, Dawn Thompson, Zhuren Wang, David Fedida, Brian Robertson

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Kv3 potassium channels, with their ultra-rapid gating and high activation threshold, are essential for high-frequency firing in many CNS neurons. Significantly, the Kv3.4 subunit has been implicated in the major CNS disorders Parkinson's and Alzheimer's diseases, and it is claimed that selectively targeting this subunit will have therapeutic utility. Previous work suggested that BDS toxins ("blood depressing substance," from the sea anemone Anemonia sulcata) were specific blockers for rapidly inactivating Kv3.4 channels, and consequently these toxins are increasingly used as diagnostic agents for Kv3.4 subunits in central neurons. However, precisely how selective are these toxins for this important CNS protein? We show that BDS is not selective for Kv3.4 but markedly inhibits current through Kv3.1 and Kv3.2 channels. Inhibition comes about not by "pore block" but by striking modification of Kv3 gating kinetics and voltage dependence. Activation and inactivation kinetics are slowed by BDS-I and BDS-II, and V(1/2) for activation is shifted to more positive voltages. Alanine substitution mutagenesis around the S3b and S4 segments of Kv3.2 reveals that BDS acts via voltage-sensing domains, and, consistent with this, ON gating currents from nonconducting Kv3.2 are markedly inhibited. The altered kinetics and gating properties, combined with lack of subunit selectivity with Kv3 subunits, seriously affects the usefulness of BDS toxins in CNS studies. Furthermore, our results do not easily fit with the voltage sensor "paddle" structure proposed recently for Kv channels. Our data will be informative for experiments designed to dissect out the roles of Kv3 subunits in CNS function and dysfunction.

Original languageEnglish
Pages (from-to)8735-45
Number of pages11
JournalJournal of Neuroscience
Volume25
Issue number38
DOIs
Publication statusPublished - 21 Sep 2005

Fingerprint

Sea Anemones
Potassium
Shaw Potassium Channels
Neurons
Mutagenesis
Alanine
Parkinson Disease
Alzheimer Disease
Proteins
Therapeutics

Keywords

  • Animals
  • Cell Line
  • Central Nervous System
  • Cnidarian Venoms
  • Electrophysiology
  • Humans
  • Neurotoxins
  • Potassium Channel Blockers
  • Rats
  • Sea Anemones
  • Shaw Potassium Channels

Cite this

Modulation of Kv3 subfamily potassium currents by the sea anemone toxin BDS : significance for CNS and biophysical studies. / Yeung, Shuk Yin M; Thompson, Dawn; Wang, Zhuren; Fedida, David; Robertson, Brian.

In: Journal of Neuroscience, Vol. 25, No. 38, 21.09.2005, p. 8735-45.

Research output: Contribution to journalArticle

Yeung, Shuk Yin M ; Thompson, Dawn ; Wang, Zhuren ; Fedida, David ; Robertson, Brian. / Modulation of Kv3 subfamily potassium currents by the sea anemone toxin BDS : significance for CNS and biophysical studies. In: Journal of Neuroscience. 2005 ; Vol. 25, No. 38. pp. 8735-45.
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abstract = "Kv3 potassium channels, with their ultra-rapid gating and high activation threshold, are essential for high-frequency firing in many CNS neurons. Significantly, the Kv3.4 subunit has been implicated in the major CNS disorders Parkinson's and Alzheimer's diseases, and it is claimed that selectively targeting this subunit will have therapeutic utility. Previous work suggested that BDS toxins ({"}blood depressing substance,{"} from the sea anemone Anemonia sulcata) were specific blockers for rapidly inactivating Kv3.4 channels, and consequently these toxins are increasingly used as diagnostic agents for Kv3.4 subunits in central neurons. However, precisely how selective are these toxins for this important CNS protein? We show that BDS is not selective for Kv3.4 but markedly inhibits current through Kv3.1 and Kv3.2 channels. Inhibition comes about not by {"}pore block{"} but by striking modification of Kv3 gating kinetics and voltage dependence. Activation and inactivation kinetics are slowed by BDS-I and BDS-II, and V(1/2) for activation is shifted to more positive voltages. Alanine substitution mutagenesis around the S3b and S4 segments of Kv3.2 reveals that BDS acts via voltage-sensing domains, and, consistent with this, ON gating currents from nonconducting Kv3.2 are markedly inhibited. The altered kinetics and gating properties, combined with lack of subunit selectivity with Kv3 subunits, seriously affects the usefulness of BDS toxins in CNS studies. Furthermore, our results do not easily fit with the voltage sensor {"}paddle{"} structure proposed recently for Kv channels. Our data will be informative for experiments designed to dissect out the roles of Kv3 subunits in CNS function and dysfunction.",
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T1 - Modulation of Kv3 subfamily potassium currents by the sea anemone toxin BDS

T2 - significance for CNS and biophysical studies

AU - Yeung, Shuk Yin M

AU - Thompson, Dawn

AU - Wang, Zhuren

AU - Fedida, David

AU - Robertson, Brian

PY - 2005/9/21

Y1 - 2005/9/21

N2 - Kv3 potassium channels, with their ultra-rapid gating and high activation threshold, are essential for high-frequency firing in many CNS neurons. Significantly, the Kv3.4 subunit has been implicated in the major CNS disorders Parkinson's and Alzheimer's diseases, and it is claimed that selectively targeting this subunit will have therapeutic utility. Previous work suggested that BDS toxins ("blood depressing substance," from the sea anemone Anemonia sulcata) were specific blockers for rapidly inactivating Kv3.4 channels, and consequently these toxins are increasingly used as diagnostic agents for Kv3.4 subunits in central neurons. However, precisely how selective are these toxins for this important CNS protein? We show that BDS is not selective for Kv3.4 but markedly inhibits current through Kv3.1 and Kv3.2 channels. Inhibition comes about not by "pore block" but by striking modification of Kv3 gating kinetics and voltage dependence. Activation and inactivation kinetics are slowed by BDS-I and BDS-II, and V(1/2) for activation is shifted to more positive voltages. Alanine substitution mutagenesis around the S3b and S4 segments of Kv3.2 reveals that BDS acts via voltage-sensing domains, and, consistent with this, ON gating currents from nonconducting Kv3.2 are markedly inhibited. The altered kinetics and gating properties, combined with lack of subunit selectivity with Kv3 subunits, seriously affects the usefulness of BDS toxins in CNS studies. Furthermore, our results do not easily fit with the voltage sensor "paddle" structure proposed recently for Kv channels. Our data will be informative for experiments designed to dissect out the roles of Kv3 subunits in CNS function and dysfunction.

AB - Kv3 potassium channels, with their ultra-rapid gating and high activation threshold, are essential for high-frequency firing in many CNS neurons. Significantly, the Kv3.4 subunit has been implicated in the major CNS disorders Parkinson's and Alzheimer's diseases, and it is claimed that selectively targeting this subunit will have therapeutic utility. Previous work suggested that BDS toxins ("blood depressing substance," from the sea anemone Anemonia sulcata) were specific blockers for rapidly inactivating Kv3.4 channels, and consequently these toxins are increasingly used as diagnostic agents for Kv3.4 subunits in central neurons. However, precisely how selective are these toxins for this important CNS protein? We show that BDS is not selective for Kv3.4 but markedly inhibits current through Kv3.1 and Kv3.2 channels. Inhibition comes about not by "pore block" but by striking modification of Kv3 gating kinetics and voltage dependence. Activation and inactivation kinetics are slowed by BDS-I and BDS-II, and V(1/2) for activation is shifted to more positive voltages. Alanine substitution mutagenesis around the S3b and S4 segments of Kv3.2 reveals that BDS acts via voltage-sensing domains, and, consistent with this, ON gating currents from nonconducting Kv3.2 are markedly inhibited. The altered kinetics and gating properties, combined with lack of subunit selectivity with Kv3 subunits, seriously affects the usefulness of BDS toxins in CNS studies. Furthermore, our results do not easily fit with the voltage sensor "paddle" structure proposed recently for Kv channels. Our data will be informative for experiments designed to dissect out the roles of Kv3 subunits in CNS function and dysfunction.

KW - Animals

KW - Cell Line

KW - Central Nervous System

KW - Cnidarian Venoms

KW - Electrophysiology

KW - Humans

KW - Neurotoxins

KW - Potassium Channel Blockers

KW - Rats

KW - Sea Anemones

KW - Shaw Potassium Channels

U2 - 10.1523/JNEUROSCI.2119-05.2005

DO - 10.1523/JNEUROSCI.2119-05.2005

M3 - Article

VL - 25

SP - 8735

EP - 8745

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 38

ER -