Enhancement Effects of Martentoxin on Glioma BK Channel and BK Channel (α+β1) Subtypes

Abstract

BackgroundBK channels are usually activated by membrane depolarization and cytoplasmic Ca2+. Especially,the activity of BK channel (α+β4) can be modulated by martentoxin, a 37 residues peptide, with Ca2+-dependent manner. gBK channel (glioma BK channel) and BK channel (α+β1) possessed higher Ca2+ sensitivity than other known BK channel subtypes.Methodology and Principal FindingsThe present study investigated the modulatory characteristics of martentoxin on these two BK channel subtypes by electrophysiological recordings, cell proliferation and Ca2+ imaging. In the presence of cytoplasmic Ca2+, martentoxin could enhance the activities of both gBK and BK channel (α+β1) subtypes in dose-dependent manner with EC50 of 46.7 nM and 495 nM respectively, while not shift the steady-state activation of these channels. The enhancement ratio of martentoxin on gBK and BK channel (α+β1) was unrelated to the quantitive change of cytoplasmic Ca2+ concentrations though the interaction between martentoxin and BK channel (α+β1) was accelerated under higher cytoplasmic Ca2+. The selective BK pore blocker iberiotoxin could fully abolish the enhancement of these two BK subtypes induced by martentoxin, suggesting that the auxiliary β subunit might contribute to the docking for martentoxin. However, in the absence of cytoplasmic Ca2+, the activity of gBK channel would be surprisingly inhibited by martentoxin while BK channel (α+β1) couldn't be affected by the toxin.Conclusions and SignificanceThus, the results shown here provide the novel evidence that martentoxin could increase the two Ca2+-hypersensitive BK channel subtypes activities in a new manner and indicate that β subunit of these BK channels plays a vital role in this enhancement by martentoxin.

Subtype-Selective Activation of Kv7 Channels by AaTXKβ(2–64), a Novel Toxin Variant from theAndroctonus australisScorpion Venom

“…This ability has been previously described for martentoxin (MarTx), an a-KTx purified from the East-Asian scorpion Mesobuthus martensi venom, which enhances the activities of native and cloned BK channels (Tao et al, 2011), and DkTx (double-knot toxin) purified from the venom of the Chinese bird tarantula Ornithoctonus huwena, which selectively and irreversibly activates transient receptor potential vanilloid-1 channels (Bohlen et al, 2010). Notably, a MarTx variant (MarTx-1) lacking of the N-terminal phenylalanine displayed similar biologic activities when compared with the full-length MarTx (Cao et al, 2003b).…”

Conopeptide Vt3.1 Preferentially Inhibits BK Potassium Channels Containing β4 Subunits via Electrostatic Interactions

“…Similar to ChTx and IbTx, ␤4 reduced inhibition by slotoxin (40). Martentoxin, on the other hand, showed a more complex behavior such that it enhanced currents of BK channels in association with the ␤1 or ␤4 subunit in the presence of high (20 M) intracellular Ca 2ϩ currents while inhibiting the channel with the ␤4 subunit in the presence of low (10 -500 nM) Ca 2ϩ (41,42). Because ␤4 is the major BK channel ␤ subunit in brain, these properties render the existing toxins ineffective as a tool in studying BK channels in neuroscience.…”

Scorpion toxin peptide action at the ion channel subunit level

“…Martentoxin (Buthus martensii Karsch) was the only peptide to show excitatory effects on human glioma and hSloa with b1, again showing modulation of action by the presence of b subunits (Tao et al, 2011).…”

“…Inhibit current, Rabbit PCT, K d ¼ 0.5 mM, (Tauc et al, 1993); Inhibit current, Bovine aortic smooth muscle, IC 50 ¼ 250 pM, (Galvez et al, 1990); Inhibit current, Mouse mSlo1, Xenopus oocytes, EC 50 ¼ 9.1 nM, (Gribkoff et al, 1996); Inhibit current, Human gBK, U251 glioma cells, 100 nM, (Tao et al, 2011); Inhibit current, Human hSlo(a), Xenopus oocytes, EC 50 ¼ 7.9 nM, (Gribkoff et al, 1996) Scorpio maurus palmatus Inhibit current, Human RBC, IC 50 ¼ 50 nM, (Castle et al, 2003); Inhibit current, Human, CHO, IC 50 ¼ 1.1 nM, (Castle et al, 2003) Inhibit current, Human, Jurkat, (Shakkottai et al, 2001) Inhibit current, Human, COS7, Inhibit current, Rat, HEK293, 1 mM, Inhibit current, Human, HEK293, 1 mM, (Chen et al, 2015) Slotoxina KTx1.11…”