Discrepin

Last updated March 25, 2019

Discrepin (α-KTx15.6) is a peptide from the venom of the Venezuelan scorpion Tityus discrepans.^[1] It acts as a neurotoxin by irreversibly blocking A-type voltage-dependent K⁺-channels.

Peptides are short chains of amino acid monomers linked by peptide (amide) bonds.

Venom form of toxin secreted by an animal for the purpose of causing harm to another; poisonous substance injected by animals into a victim

Venom is a secretion containing one or more toxins produced by an animal to cause harm to another. Venom has evolved in a wide variety of animals, both predators and prey, and both vertebrates and invertebrates.

Neurotoxins are toxins that are destructive to nerve tissue. Neurotoxins are an extensive class of exogenous chemical neurological insults that can adversely affect function in both developing and mature nervous tissue. The term can also be used to classify endogenous compounds, which, when abnormally contacted, can prove neurologically toxic. Though neurotoxins are often neurologically destructive, their ability to specifically target neural components is important in the study of nervous systems. Common examples of neurotoxins include lead, ethanol, manganese glutamate, nitric oxide, botulinum toxin, tetanus toxin, and tetrodotoxin. Some substances such as nitric oxide and glutamate are in fact essential for proper function of the body and only exert neurotoxic effects at excessive concentrations.

Etymology and source

Discrepin is named after its source: a Venezuelan scorpion called Tityus discrepans .^[1] Its systematic number is α-KTx15.6.^[2]

Tityus is a large genus of thick-tailed scorpions, the namesake of its subfamily Tityinae. As of June 2012, Tityus contains more than 200 described species distributed in Central America and South America, from Costa Rica to Argentina.

Chemistry

The subfamily α-KTx15 consists of 6 toxins. The first five toxins of this subfamily are very much alike, but discrepin only shares 50% amino acid homology with other members of this subfamily.^[1] Discrepin contains 38 amino acid residues. It has a polyglutamic acid at its N-terminal region.^[3] Discrepin has the α and β folds that are characteristic of scorpion toxins.^[2] It consists of one α-helix and three β-sheet helix strands. The α-helix is formed from amino acid Ser11 until Arg21. The three antiparallel β-sheets are formed from amino acid Ile2 until Lys7, Ala27 until Cys29 and Arg33 until Cys36.

Scorpion toxins are proteins found in the venom of scorpions. Their toxic effect may be mammal- or insect-specific and acts by binding to sodium channels, inhibiting the inactivation of activated channels and blocking neuronal transmission.

Target

Discrepin blocks voltage-gated Shal-type (Kv4.x) K⁺ channels in cerebellar granular cells.^[1]^[2] These A-type K⁺ channels regulate firing frequency, spike initiation and the waveform of action potentials.^[2] Discrepin has yet only been tested in cerebellar cells, however, Kv4.x family channels are in general highly expressed in the brain, heart and smooth muscles.^[4] Competition experiments showed that discrepin inhibits the binding of scorpion toxin BmTx3 to its receptor site, where other K⁺ channel blockers (Kv1-, Kv3.4-, Kv4.2/4.3 family blockers) were unable to compete with this toxin. These results support the hypothesis that discrepin can bind to a very specific and unique type of Kv4.x receptor channels.^[2] The residues of discrepin that are important for blocking these channels have not yet been clarified. However, it is clear that the N-terminal plays a role in the binding affinity.^[3] The stoichiometry of toxin binding to the potassium channel is 1:1.^[3]

The name granule cell has been used for a number of different types of neuron whose only common feature is that they all have very small cell bodies. Granule cells are found within the granular layer of the cerebellum, the dentate gyrus of the hippocampus, the superficial layer of the dorsal cochlear nucleus, the olfactory bulb, and the cerebral cortex.

In physiology, an action potential occurs when the membrane potential of a specific axon location rapidly rises and falls: this depolarisation then causes adjacent locations to similarly depolarise. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, endocrine cells, and in some plant cells.

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.

Mode of action

Discrepin specifically blocks the I_A currents (fast transient, low-voltage-activated currents) of voltage-dependent K+ channels. Inhibition of these K⁺ currents occurs in an irreversible manner, i.e. washing out of the toxin gives no recovery of the currents.^[1]^[2] The kinetics of the channel are not affected by discrepin and the blockage is independent of the holding potential.^[2]

Toxicity

The half-effective dose (IC50) is 190 ± 30 nM.^[1]

Related Research Articles

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References

1 2 3 4 5 6 D'Suze G, Batista CV, Frau A, et al. (October 2004). "Discrepin, a new peptide of the sub-family alpha-ktx15, isolated from the scorpion Tityus discrepans irreversibly blocks K+ -channels (IA currents) of cerebellum granular cells". Archives of Biochemistry and Biophysics. 430 (2): 256–63. doi:10.1016/j.abb.2004.07.010. PMID 15369825.
1 2 3 4 5 6 7 Prochnicka-Chalufour A, Corzo G, Satake H, et al. (February 2006). "Solution structure of discrepin, a new K+-channel blocking peptide from the alpha-KTx15 subfamily". Biochemistry. 45 (6): 1795–804. doi:10.1021/bi0519248. PMID 16460026.
1 2 3 Romeo S, Corzo G, Vasile A, Satake H, Prestipino G, Possani LD (April 2008). "A positive charge at the N-terminal segment of Discrepin increases the blocking effect of K+ channels responsible for the IA currents in cerebellum granular cells". Biochimica et Biophysica Acta. 1780 (4): 750–5. doi:10.1016/j.bbagen.2008.01.012. PMID 18280256.
↑ Birnbaum SG, Varga AW, Yuan LL, Anderson AE, Sweatt JD, Schrader LA (July 2004). "Structure and function of Kv4-family transient potassium channels". Physiological Reviews. 84 (3): 803–33. doi:10.1152/physrev.00039.2003. PMID 15269337.

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[pmid15369825-1] 1 2 3 4 5 6 D'Suze G, Batista CV, Frau A, et al. (October 2004). "Discrepin, a new peptide of the sub-family alpha-ktx15, isolated from the scorpion Tityus discrepans irreversibly blocks K+ -channels (IA currents) of cerebellum granular cells". Archives of Biochemistry and Biophysics. 430 (2): 256–63. doi:10.1016/j.abb.2004.07.010. PMID 15369825.

[pmid16460026-2] 1 2 3 4 5 6 7 Prochnicka-Chalufour A, Corzo G, Satake H, et al. (February 2006). "Solution structure of discrepin, a new K+-channel blocking peptide from the alpha-KTx15 subfamily". Biochemistry. 45 (6): 1795–804. doi:10.1021/bi0519248. PMID 16460026.

[pmid18280256-3] 1 2 3 Romeo S, Corzo G, Vasile A, Satake H, Prestipino G, Possani LD (April 2008). "A positive charge at the N-terminal segment of Discrepin increases the blocking effect of K+ channels responsible for the IA currents in cerebellum granular cells". Biochimica et Biophysica Acta. 1780 (4): 750–5. doi:10.1016/j.bbagen.2008.01.012. PMID 18280256.

[pmid15269337-4] Birnbaum SG, Varga AW, Yuan LL, Anderson AE, Sweatt JD, Schrader LA (July 2004). "Structure and function of Kv4-family transient potassium channels". Physiological Reviews. 84 (3): 803–33. doi:10.1152/physrev.00039.2003. PMID 15269337.