Stichodactyla helianthus Peptide, a Pharmacological Tool for Studying Kv3.2 Channels

Voltage-gated potassium (Kv) channels regulate many physiological functions and represent important therapeutic targets in the treatment of several clinical disorders. Although some of these channels have been well-characterized, the study of others, such as Kv3 channels, has been hindered because o...

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Bibliographic Details
Published in:Molecular pharmacology 2005-05, Vol.67 (5), p.1513-1521
Main Authors: Yan, Lizhen, Herrington, James, Goldberg, Ethan, Dulski, Paula M, Bugianesi, Randal M, Slaughter, Robert S, Banerjee, Priya, Brochu, Richard M, Priest, Birgit T, Kaczorowski, Gregory J, Rudy, Bernardo, Garcia, Maria L
Format: Article
Language:English
Subjects:
Animals
CHO Cells
Cnidarian Venoms - isolation & purification
Cnidarian Venoms - pharmacology
Cricetinae
Dose-Response Relationship, Drug
Female
Humans
In Vitro Techniques
Islets of Langerhans - drug effects
Islets of Langerhans - metabolism
Mice
Peptide Fragments - isolation & purification
Peptide Fragments - pharmacology
Potassium Channel Blockers - isolation & purification
Potassium Channel Blockers - pharmacology
Potassium Channels, Voltage-Gated - antagonists & inhibitors
Potassium Channels, Voltage-Gated - biosynthesis
Sea Anemones
Shaw Potassium Channels
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Summary:Voltage-gated potassium (Kv) channels regulate many physiological functions and represent important therapeutic targets in the treatment of several clinical disorders. Although some of these channels have been well-characterized, the study of others, such as Kv3 channels, has been hindered because of limited pharmacological tools. The current study was initiated to identify potent blockers of the Kv3.2 channel. Chinese hamster ovary (CHO)-K1 cells stably expressing human Kv3.2b (CHO-K1.hKv3.2b) were established and characterized. Stichodactyla helianthus peptide (ShK), isolated from S. helianthus venom and a known high-affinity blocker of Kv1.1 and Kv1.3 channels, was found to potently inhibit 86 Rb + efflux from CHO-K1.hKv3.2b (IC 50 ∼ 0.6 nM). In electrophysiological recordings of Kv3.2b channels expressed in Xenopus laevis oocytes or in planar patch-clamp studies, ShK inhibited hKv3.2b channels with IC 50 values of ∼0.3 and 6 nM, respectively. Despite the presence of Kv3.2 protein in human pancreatic β cells, ShK has no effect on the Kv current of these cells, suggesting that it is unlikely that homotetrameric Kv3.2 channels contribute significantly to the delayed rectifier current of insulin-secreting cells. In mouse cortical GABAergic fast-spiking interneurons, however, application of ShK produced effects consistent with the blockade of Kv3 channels (i.e., an increase in action potential half-width, a decrease in the amplitude of the action potential after hyperpolarization, and a decrease in maximal firing frequency in response to depolarizing current injections). Taken together, these results indicate that ShK is a potent inhibitor of Kv3.2 channels and may serve as a useful pharmacological probe for studying these channels in native preparations.
ISSN:0026-895X
1521-0111
DOI:10.1124/mol.105.011064