BmTx3 is a neurotoxin, which is a component of the venom of the scorpion Buthus Martensi Karsch. It blocks A-type potassium channels in the central nervous system and hERG-channels in the heart.

Source/Isolation

BmTx3 was originally purified from the venom of the Chinese scorpion, Buthus Martensi Karsch. BmTx3 is a “short-chain” peptide like other potassium channel blockers in the scorpion venom and added to the phylogenetic tree in the subfamily α-KTx15. Its 3D structure has not yet been elucidated, but based on sequence similarity it likely resembles the 3D structure of BmTx1 [1] or Discrepin.[2]

Biochemistry

BmTx3 consists of an α-helix and two β-sheet segments cross-linked by three disulfide bridges (Cs-α/β motif).[1] It is a short chain peptide with a molecular mass of 3751.6 Da; it consists of 37 amino acids.[1]

α/β motif of BmTx3

Target

BmTx3 is the first toxin from the scorpion α-KTx subfamily 15 [3] with two functional faces. As all α-KTx peptides, BmTx3 blocks A-type (IA) potassium currents (KD = 54 nM). BmTx3 blocks primarily the Kv4.x proteins and has a higher affinity for Kv4.1 channels than for Kv4.2 and Kv4.3 channels.[4] The second functional face of BmTx3 blocks the hERG (human Ether-à-go-go) channel (KD = 2 μM), a characteristic belonging to γ-KTx peptides.[4] BmTx3 binding site seems essentially localized in neurons but could also be present in glial cells, endothelial cells and/or arterial smooth muscle cells. The distribution of BmTx3 binding sites is heterogeneous; a high density is found in the caudate–putamen and accumbens nucleus, thalamus, hippocampal formation and cerebellum.[4]

Mode of Action

The functional face of “short-chain” scorpion toxins is built of two important dyads (Lys and Tyr) on the β-sheet side. Lysine plugs deep into the channel pore and Tyrosine, as penultimate or ultimate and hydrophobic residue, turns it to fixate it, leading to a physical occlusion of the channel pore.[1] This is supported by the finding that deletion of the two C-terminal residues (sBmTx3-delYP) results in loss of ability to block IA-current.[1]

The other functional face is thought to be situated at the α-helix-side and composed of Arg18 and Lys19, like the functional face of other hERG toxins. It is known that α-KTx peptides use the β-sheet side to interact with the receptor, whereas γ-KTx peptides usually use their α-helix-side.[5] As BmTx3 seems to use both sides to bind to different potassium channels, it might be an evolutionary transient between the two families.[5]

Toxicity

When injected into mice it causes epileptiform behavior.[6] This might be due to its effect on A-type K+ channels, which, like the Kv4.x, are involved in action potential back propagation, firing frequency, spike initiation and action potential waveform determination.[4] Blocking of the hERG channel can cause drug-induced long QT syndrome, arrhythmias and ventricular fibrillation which can result in death.[5]

References

  1. ^ a b c d e Vacher, H. (2003). "Functional consequences of deleting the two C-terminal residues of the scorpion toxin BmTX3". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1646 (1–2): 152–156. doi:10.1016/S1570-9639(02)00557-5. PMID 12637022.
  2. ^ Prestipino, G. (2009). "Scorpion toxins that block transient currents (I(A)) of rat cerebellum granular cells". Toxicology Letters. 187 (1): 1–9. doi:10.1016/j.toxlet.2009.01.027. PMID 19429236.
  3. ^ Vacher, H. (2004). "Definition of the alpha-KTx15 subfamily". Toxicon. 43 (8): 887–94. doi:10.1016/j.toxicon.2004.03.023. PMID 15208021.
  4. ^ a b c d Vacher, H. (2006). "Kv4 channels sensitive to BmTX3 in rat nervous system: autoradiographic analysis of their distribution during brain ontogenesis". Eur J Neurosci. 24 (5): 1325–40. doi:10.1111/j.1460-9568.2006.05020.x. PMID 16987219. S2CID 3129580.
  5. ^ a b c Huys, I. (2004). "BmTx3, a scorpion toxin with two putative functional faces separately active on A-type K+ and HERG currents". Biochem. J. 378 (Pt 3): 745–52. doi:10.1042/BJ20031324. PMC 1223995. PMID 14599291.
  6. ^ Vacher, H. (2001). "A new class of scorpion toxin binding sites related to an A-type K+ channel: pharmacological characterization and localization in rat brain". FEBS Lett. 501 (1): 31–5. doi:10.1016/S0014-5793(01)02620-5. PMID 11457451.
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