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Enzymatic activation of voltage-gated potassium channels


Voltage-gated ion channels in excitable nerve, muscle, and endocrine cells generate electric signals in the form of action potentials1. However, they are also present in non-excitable eukaryotic cells and prokaryotes, which raises the question of whether voltage-gated channels might be activated by means other than changing the voltage difference between the solutions separated by the plasma membrane. The search for so-called voltage-gated channel activators is motivated in part by the growing importance of such agents in clinical pharmacology. Here we report the apparent activation of voltage-gated K+ (Kv) channels by a sphingomyelinase.

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Figure 1: Identification of Kv channel-stimulating activity.
Figure 2: Effects of pH, histidine mutations and Mg 2+ on SMase D activity.
Figure 3: Effect of SMase D on the G V curve of Kv2.1-Δ7 channels.
Figure 4: Effects of SMase D on other K + channels.


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We thank K. Lynch (University of Virginia) for sharing the cDNA clone of Lr2 isoform of SMase D; R. Joho and K. Swartz for Kv2.1 cDNA; G. Robertson and B. Ganetzky for mEAG cDNA; L. Salkoff and F. Horrigan for mSlo cDNA; K. Swartz for Shaker-IR cDNA in the pGEM-HESS vector and the HaTx sample; C.-X. Yuan for LC–MS/MS sequencing; J. R. Martinez-Francois for chemical structure drawing; R. MacKinnon for comments; and P. De Weer for review and discussion of our manuscript. This study was supported by a grant from the National Institute of General Medical Sciences to Z.L.

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Correspondence to Zhe Lu.

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Supplementary information

Supplementary Figure 1

LCMS/MS-identified peptide sequences match those of Lr1 and Lr2 isoforms of SMase D. (JPG 62 kb)

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Ramu, Y., Xu, Y. & Lu, Z. Enzymatic activation of voltage-gated potassium channels. Nature 442, 696–699 (2006).

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