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The Journal of Neuroscience, September 21, 2005, 25(38):8735-8745; doi:10.1523/JNEUROSCI.2119-05.2005

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Cellular/Molecular
Modulation of Kv3 Subfamily Potassium Currents by the Sea Anemone Toxin BDS: Significance for CNS and Biophysical Studies

Shuk Yin M. Yeung,¹ Dawn Thompson,¹ Zhuren Wang,² David Fedida,² and Brian Robertson¹

¹Neuroscience Group, School of Biomedical Sciences, University of Leeds, Leeds LS2 9NQ, United Kingdom, and ²Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3

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.

Key words: potassium channel; Kv3 channels; fast spiking; toxins; Parkinson's disease; BDS

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Received Jan 31, 2005; revised July 28, 2005; accepted July 28, 2005.

This article has been cited by other articles:

				Z. Wang, B. Robertson, and D. Fedida Gating currents from a Kv3 subfamily potassium channel: charge movement and modification by BDS-II toxin J. Physiol., November 1, 2007; 584(3): 755 - 767. [Abstract] [Full Text] [PDF]

				A. Pannaccione, F. Boscia, A. Scorziello, A. Adornetto, P. Castaldo, R. Sirabella, M. Taglialatela, G. F. D. Renzo, and L. Annunziato Up-Regulation and Increased Activity of KV3.4 Channels and Their Accessory Subunit MinK-Related Peptide 2 Induced by Amyloid Peptide Are Involved in Apoptotic Neuronal Death Mol. Pharmacol., September 1, 2007; 72(3): 665 - 673. [Abstract] [Full Text] [PDF]

				M. Martina, A. E. Metz, and B. P. Bean Voltage-Dependent Potassium Currents During Fast Spikes of Rat Cerebellar Purkinje Neurons: Inhibition by BDS-I Toxin J Neurophysiol, January 1, 2007; 97(1): 563 - 571. [Abstract] [Full Text] [PDF]

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