BmTx3 is aneurotoxin, which is a component of thevenom of thescorpionButhus Martensi Karsch. It blocks A-typepotassium channels in thecentral nervous system andhERG-channels in the heart.
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 thephylogenetic 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] orDiscrepin.[2]
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 37amino acids.[1]
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 inneurons but could also be present inglial cells,endothelial cells and/or arterial smooth muscle cells. The distribution of BmTx3 binding sites is heterogeneous; a high density is found in thecaudate–putamen andaccumbens nucleus,thalamus,hippocampal formation andcerebellum.[4]
The functional face of “short-chain” scorpion toxins is built of two importantdyads (Lys and Tyr) on the β-sheet side.Lysine plugs deep into the channel pore andTyrosine, as penultimate or ultimate andhydrophobic 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 twoC-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]
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 inaction potential back propagation, firing frequency, spike initiation and action potential waveform determination.[4]Blocking of the hERG channel can cause drug-inducedlong QT syndrome, arrhythmias andventricular fibrillation which can result in death.[5]
