BgK

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BgK is a neurotoxin found within secretions of the sea anemone Bunodosoma granulifera which blocks voltage-gated potassium channels, thus inhibiting neuronal repolarization.

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Etymology

The neurotoxin was named BgK, with the Bg representing the Latin taxonomy ( Bunodosoma granulifera) of the specific sea anemone from which the toxin was found, and the K standing for the chemical symbol for potassium owing to its observed effects on K+ channels.

Sources in Nature

BgK can be found in the mucus of the Bunodosoma granulifera, a common sea anemone found along the coasts of Cuba. Since it is a contracting sea anemone, it has two forms based on the position of its tentacles: open and closed. BgK is released when the anemone is in the closed form, a position it assumes during the day or during times of agitation. In this form, the anemone’s tentacles retract, releasing a mucus from a fibrous matrix found in the mesoglea, a space between the ectodermis and the gastrodermis. For every gram of freeze-dried mucus, there is 0.5 mg BgK. [1]

Chemistry

BgK is composed of 37 amino acid residues, and three disulfide bonds. [1] [2] The neurotoxin belongs to a family of toxins found within 3 different sea anemones. The two other anemone/toxin combinations are: Stichodactyla helianthus and ShK; Anemonia viridis and AsKs. All three of these toxins have an affinity to dendrotoxin sensitive potassium channels that are found within rat brain membranes. BgK and ShK attenuate K+ channels in the neurons of rat dorsal ganglia, in vitro. [1] [3] AsKs stops potassium channel currents that are present in Xenopus oocytes. [4] These toxins potentially represent a new structural type of potassium channel inhibitor. Compared to the short and well-studied scorpion toxins, these anemone toxins have comparable amino acid content (35-37 residues) and the same number of disulfide bridges (three). However, these anemone toxins do not share any sequential similarity. Specifically, the different position of the cysteine residues found within these toxins suggests that BgK, ShK, and AsKS are a new family of toxins. [2]

The only homology BgK shares is with a double-headed protease inhibitor found in sea turtles, however it is only limited to a part of the inhibitor, with the largest similarity found with the cysteine residues, which compose six of the eight conserved amino acids found in the two sequences. [1]

Target

BgK blocks the Kv1.1, Kv1.2, and Kv1.3 channels with similar affinities. [5] IC50 is 6 nM for Kv1.1, 15 nM for Kv1.2, and 10 nM for Kv1.3. [2] Meanwhile, tests on the Kv3 channel, specifically Kv3.1, show that the ion channel exhibits an insensitivity of up to 0.125 μM BgK. [2]

Mode of Action

BgK competes with I-α-dendrotoxin, a known probe used to indicate the presence of certain potassium channels, over binding to synaptic membranes within rat brains. [1] The binding sites of the toxin between Kv1.1, Kv1.2, and Kv1.3 were found to include three common amino acid residues: Lys-25, Tyr-26, and Ser-23. [5] This combination appear to form the core residues that are the site of binding of all Kv1 channel blockers from sea anemones. [5] In particular with Kv1.1, the major reason for BgK's affinity towards binding to this specific channel stems from an electrostatic connections between the side chain of Lys-25 and the carbonyl oxygens of the amino acids found within the channel's molecular filter. [6] Another aspect of BgK's binding to Kv1.1 involves the hydrophobic reactions between Tyr-379 of Kv1.1 and the dyad of Tyr-26 and Phe-6 formed within BgK. [6] Such interactions have been found to surround the Lys-25 and could potentially strengthen the electrostatic interactions that can form between this specific lysine and the oxygen atoms of the channel's filter. [6]

Toxicity

The median lethal dose (LD50) of BgK for mice is 4.5 ng per gram. [2] Symptoms observed include trembling of the tail, muscle twitch, salivation, and paralysis, which are the generally observed physical manifestation of potassium channel blockers . [2]

Therapeutic Use

While BgK has been produced in Escherichia coli as a functional protein, exhibiting all of the effects on potassium channels found with BgK isolated from its natural source, there has been no research into any potential therapeutic purpose so far, with most of its use being for research on potassium channels. [7]

Related Research Articles

<span class="mw-page-title-main">Dendrotoxin</span> Chemical compound

Dendrotoxins are a class of presynaptic neurotoxins produced by mamba snakes (Dendroaspis) that block particular subtypes of voltage-gated potassium channels in neurons, thereby enhancing the release of acetylcholine at neuromuscular junctions. Because of their high potency and selectivity for potassium channels, dendrotoxins have proven to be extremely useful as pharmacological tools for studying the structure and function of these ion channel proteins.

<span class="mw-page-title-main">Sea anemone neurotoxin</span>

Sea anemone neurotoxin is the name given to neurotoxins produced by sea anemones with related structure and function. Sea anemone neurotoxins can be divided in two functional groups that either specifically target the sodium channel or the potassium channel.

AETX refers to a group of polypeptide neurotoxins isolated from the sea anemone Anemonia erythraea that target ion channels, altering their function. Four subtypes have been identified: AETX I, II, III and K, which vary in their structure and target.

Hemitoxin (HTX; α-KTx6.15) is a 35-mer basic peptide from the venom of the Iranian scorpion Hemiscorpius lepturus, which reversibly blocks Kv1.1, Kv1.2 and Kv1.3voltage-gated K+ channels.

Halcurin is a polypeptide neurotoxin from the sea anemone Halcurias sp. Based on sequence homology to type 1 and type 2 sea anemone toxins it is thought to delay channel inactivation by binding to the extracellular site 3 on the voltage gated sodium channels in a membrane potential-dependent manner.

Parabutoxin (PBTx) is a Shaker-related voltage-gated K+ channel (Kvα1) inhibitor purified from different Parabuthus scorpion species found in southern Africa. It occurs in different forms: parabutoxin 1 (PBTx1), parabutoxin 2 (PBTx2), parabutoxin 3 (PBTx3) and parabutoxin (PBTx10). The different variants have different affinities towards Kvα1 channels.

Anuroctoxin is a peptide from the venom of the Mexican scorpion Anuroctonus phaiodactylus. This neurotoxin belongs to the alpha family of potassium channel acting peptides. It is a high-affinity blocker of Kv1.3 channels.

Cangitoxin, also known as CGTX or CGX, is a toxin purified from the venom of the sea anemone Bunodosoma cangicum, which most likely acts by prolonging the inactivation of voltage-gated sodium channels.

Tamulotoxin is a venomous neurotoxin from the Indian Red Scorpion.

Kaliseptine (AsKS) is a neurotoxin which can be found in the snakelocks anemone Anemonia viridis. It belongs to a class of sea anemone neurotoxins that inhibits voltage-gated potassium channels.

HsTx1 is a toxin from the venom of the scorpion Heterometrus spinifer. HsTx1 is a very potent inhibitor of the rat Kv1.3 voltage-gated potassium channel.

Spinoxin is a 34-residue peptide neurotoxin isolated from the venom of the Malaysian black scorpion Heterometrus spinifer. It is part of the α-KTx6 subfamily and exerts its effects by inhibiting voltage-gated potassium channels, specifically Kv1.2 and Kv1.3.

HgeTx1 (systematic name: α-KTx 6.14) is a toxin produced by the Mexican scorpion Hoffmanihadrurus gertschi that is a reversible blocker of the Shaker B K+-channel, a type of voltage-gated potassium channels.

SHTX is a toxin derived from the sea anemone Stichodactyla haddoni; there are four different subtypes, SHTX I, II, III and IV. SHTX I, II and III can paralyze crabs by acting on potassium channels, while SHTX IV works on sodium channels, and is lethal to crabs.

Kalicludine (AsKC) is a blocker of the voltage-dependent potassium channel Kv1.2 found in the snakeslocks anemone Anemonia viridis, which it uses to paralyse prey.

BmP02, also known as α-KTx 9.1 or Bmkk(6), is a toxin from the Buthus Martensi Karsch (BmK) scorpion. The toxin acts on potassium channels, blocking Kv1.3 and slowing the deactivation of Kv4.2. BmP02 is not toxic to humans or mice.

<span class="mw-page-title-main">BscTx3</span>

BcsTx3, also known as Kappa-actitoxin-Bsc4a, is a neurotoxin that blocks voltage-gated potassium channel (Kv1/KCNA). It is purified from the venom of Bunodosoma caissarum.

AsKC11 is a toxin found in the venom of the sea anemone, Anemonia sulcata. This toxin is part of the Kunitz peptide family and has been shown to be an activator of G protein-coupled inwardly-rectifying potassium (GIRK) channels 1/2, involved in the regulation of cellular excitability. 

<span class="mw-page-title-main">LmKTT-1a</span> Scorpion Toxin

LmKTT-1a is a bifunctional Kunitz-type toxin belonging to the ẟ-KTx subfamily, which can be found in the venom of Lychasmucronatus. As a bifunctional toxin, it both inhibits trypsin activity and blocks Kv1 channels with a weak selectivity towards Kv1.3 channels.

Kunitz-type serine protease inhibitor APEKTx1 is a peptide toxin derived from the sea anemone Anthopleura elegantissima. This toxin has a dual function, acting both as a serine protease inhibitor and as a selective and potent pore blocker of Kv1.1, a shaker related voltage-gated potassium channel.

References

  1. 1 2 3 4 5 Aneiros, A; García, I; Martínez, JR; Harvey, AL; Anderson, AJ; Marshal, DL; Engstöm, Å; Hellman, U; Karlsson, E (1993). "A potassium channel toxin from the secretion of the sea anemone "Bunodosoma granulifera". Isolation, amino acid sequence and biological activity". Biochimica et Biophysica Acta (BBA) - General Subjects. 1157 (1): 86–92. doi:10.1016/0304-4165(93)90082-J. PMID   8098956.
  2. 1 2 3 4 5 6 Cotton, Joel; Crest, M; Bouet, F; Alessandri, N; Gola, M; Forest, E; Karlsson, E; Castañeda, O; Harvey, AL; Vita, C; Ménez, A (1997). "A potassium channel toxin from the sea anemone Bunodosoma granulifera, an inhibitor for Kv1 channels — revision of the amino acid sequence, disulfide-bridge assignment, Chemical Synthesis, and Biological Activity". European Journal of Biochemistry. 244 (1): 192–202. doi: 10.1111/j.1432-1033.1997.00192.x . PMID   9063464.
  3. ↑ Castaneda, Olga; et al. (1995). "Characterization of a potassium channel toxin from the Caribbean Sea anemone Stichodactyla helianthus". Toxicon. 33 (5): 603–613. doi:10.1016/0041-0101(95)00013-C. PMID   7660365.
  4. ↑ Schweitz, H; Bruhn, T; Guillemare, E; Moinier, E; Lancelin, JM; Béress, L; Lazdunski, M (1995). "Kalicludines and kaliseptine. Two different classes of sea anemone toxins for voltage sensitive K+ channels". J Biol Chem. 270 (42): 25121–6. doi: 10.1074/jbc.270.42.25121 . PMID   7559645.
  5. 1 2 3 Alessandri-Haber, N; Lecoq, A; Gasparini, S; Grangier-MacMath, G; Jacquet, G; Harvey, AL; de Meiros, G; Rowan, EG; Gola, M; Ménez, A; Crest, M (1999-12-10). "Mapping the functional anatomy of BgK on Kv1.1, Kv1.2, and Kv1.3. Clues to design analogs with enhanced selectivity". J Biol Chem. 274 (50): 35653–61. doi: 10.1074/jbc.274.50.35653 . PMID   10585444.
  6. 1 2 3 Gilquin, B; Racape, J; Wrish, A; Visan, V; Lecoq, A; Grissmer, S; Ménez, A; Gasparini, S (2002-07-19). "Structure of the BgK-Kv1.1 complex based on distance restraints identified by double mutant cycles. Molecular basis for convergent evolution of Kv1 channel blockers". J Biol Chem. 277 (40): 37406–13. doi: 10.1074/jbc.M206205200 . PMID   12133841.
  7. ↑ Braud, S; Belin, P; Dassa, J; Pardo, L; Mourier, G; Caruana, A; Priest, BT; Dulski, P; Garcia, ML; Ménez, A; Boulain, J-C; Gasparini, S (2004). "BgK, a disulfide-containing sea anemone toxin blocking K+ channels, can be produced in Escherichia coli cytoplasm as a functional tagged protein". Protein Expr. Purif. 38 (1): 69–78. doi:10.1016/j.pep.2004.07.011. PMID   15477084.
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