BmTx3 is a

neurotoxin Neurotoxins are toxins that are destructive to nerve tissue (causing neurotoxicity). Neurotoxins are an extensive class of exogenous chemical neurological insultsSpencer 2000 that can adversely affect function in both developing and mature ner ...

, which is a component of the

venom Venom or zootoxin is a type of toxin produced by an animal that is actively delivered through a wound by means of a bite, sting, or similar action. The toxin is delivered through a specially evolved ''venom apparatus'', such as fangs or a sti ...

of the

scorpion Scorpions are predatory arachnids of the order Scorpiones. They have eight legs, and are easily recognized by a pair of grasping pincers and a narrow, segmented tail, often carried in a characteristic forward curve over the back and always end ...

''Buthus Martensi'' Karsch. It blocks A-type

potassium channels Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of cel ...

in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...

and

hERG hERG (the human '' Ether-à-go-go''-Related Gene) is a gene () that codes for a protein known as Kv11.1, the alpha subunit of a potassium ion channel. This ion channel (sometimes simply denoted as 'hERG') is best known for its contribution to th ...

-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 Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...

like other potassium channel blockers in the scorpion venom and added to the

phylogenetic tree A phylogenetic tree (also phylogeny or evolutionary tree Felsenstein J. (2004). ''Inferring Phylogenies'' Sinauer Associates: Sunderland, MA.) is a branching diagram or a tree showing the evolutionary relationships among various biological spec ...

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 or Discrepin.

Biochemistry

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

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

Target

BmTx3 is the first toxin from the scorpion α-KTx subfamily 15 with two functional faces. As all α-KTx peptides, BmTx3 blocks A-type (I_A) potassium currents (K_D = 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. The second functional face of BmTx3 blocks the hERG (human Ether-à-go-go) channel (K_D = 2 μM), a characteristic belonging to γ-KTx peptides. BmTx3 binding site seems essentially localized in

neurons A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...

but could also be present in

glial cells Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form mye ...

endothelial cells The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...

and/or arterial smooth muscle cells. The distribution of BmTx3 binding sites is heterogeneous; a high density is found in the caudate–

putamen The putamen (; from Latin, meaning "nutshell") is a round structure located at the base of the forebrain (telencephalon). The putamen and caudate nucleus together form the dorsal striatum. It is also one of the structures that compose the basal n ...

and accumbens nucleus,

thalamus The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all directions, ...

hippocampal formation The hippocampal formation is a compound structure in the Temporal lobe#Medial temporal lobe, medial temporal lobe of the brain. It forms a c-shaped bulge on the floor of the temporal horn of the Lateral ventricles, lateral ventricle. There is no ...

and

cerebellum The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebel ...

Mode of Action

The functional face of “short-chain” scorpion toxins is built of two important

dyad Dyad or dyade may refer to: Arts and entertainment * Dyad (music), a set of two notes or pitches * ''Dyad'' (novel), by Michael Brodsky, 1989 * ''Dyad'' (video game), 2012 * ''Dyad 1909'' and ''Dyad 1929'', ballets by Wayne McGregor Other uses ...

s (Lys and Tyr) on the β-sheet side.

Lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...

plugs deep into the channel pore and

Tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...

, as penultimate or ultimate and

hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, th ...

residue, turns it to fixate it, leading to a physical occlusion of the channel pore. This is supported by the finding that deletion of the two

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

residues (sBmTx3-delYP) results in loss of ability to block I_A-current. 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. As BmTx3 seems to use both sides to bind to different potassium channels, it might be an evolutionary transient between the two families.

Toxicity

When injected into mice it causes epileptiform behavior. This might be due to its effect on A-type K⁺ channels, which, like the Kv4.x, are involved in

action potential An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, ...

back propagation, firing frequency, spike initiation and action potential waveform determination. Blocking of the hERG channel can cause drug-induced

long QT syndrome Long QT syndrome (LQTS) is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy QT interval. It results in an increased risk of an irregular heartbeat which can result in fainting, d ...

, arrhythmias and

ventricular fibrillation Ventricular fibrillation (V-fib or VF) is an abnormal heart rhythm in which the ventricles of the heart quiver. It is due to disorganized electrical activity. Ventricular fibrillation results in cardiac arrest with loss of consciousness and no p ...

which can result in death.

References

{{DEFAULTSORT:Bmtx3 Neurotoxins Ion channel toxins