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Ctri9577 (α-KTx15.10) is a 
*
and stabilized with neurotoxin
Neurotoxins are toxins that are destructive to nervous tissue, nerve tissue (causing neurotoxicity). Neurotoxins are an extensive class of exogenous chemical neurological insult (medical), insultsSpencer 2000 that can adversely affect function ...
present in the venom of the ''Chaerilus
''Chaerilus'' is a genus of scorpions in the family Chaerilidae. They live in tropical parts of South Asia and Southeast Asia. A fossil genus '' Electrochaerilus'' is known from the Late Cretaceous (Cenomanian) aged Burmese amber.
Description
T ...
tricostatus'' scorpion, which is a potent blocker of the voltage-gated potassium channel
Voltage-gated potassium channels (VGKCs) are potassium channel, transmembrane channels specific for potassium and Voltage-gated ion channel, sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a ...
Kv1.3, and a gating modifier of Kv4.3 channels.
*
Etymology and Source
The Ctri9577 toxin is a component of the venom of the scorpion ''Chaerilus
''Chaerilus'' is a genus of scorpions in the family Chaerilidae. They live in tropical parts of South Asia and Southeast Asia. A fossil genus '' Electrochaerilus'' is known from the Late Cretaceous (Cenomanian) aged Burmese amber.
Description
T ...
tricostatus''.
The name of the toxin derives from the first letter of the genus of ''Chaerilus'' (C), species (tri), and the clone number in the cDNA library (9577).
Chemistry
Ctri9577 is a member of the α-KTx15 subfamily, which specifically targetpotassium channel
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 ...
s. The mature peptide of Ctri9577, which is the peptide without the signal sequence, consists of 39 amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s (4.44 kDa), including six cysteines which form three disulfide bridges
In chemistry, a disulfide (or disulphide in British English) is a compound containing a functional group or the anion. The linkage is also called an SS-bond or sometimes a disulfide bridge and usually derived from two thiol groups.
In inorg ...
(see table 1). Other scorpion toxins specific for K+ channels (KTx) commonly form a CSα/β (cysteine-stabilized α-helix-β-sheet) fold. β-sheets
The beta sheet (β-sheet, also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gener ...disulfide bridges
In chemistry, a disulfide (or disulphide in British English) is a compound containing a functional group or the anion. The linkage is also called an SS-bond or sometimes a disulfide bridge and usually derived from two thiol groups.
In inorg ...
.
The predicted secondary structure
Protein secondary structure is the local spatial conformation of the polypeptide backbone excluding the side chains. The two most common Protein structure#Secondary structure, secondary structural elements are alpha helix, alpha helices and beta ...
of Ctri9577 is based on the typical fold of other scorpion KTxs; it consists of an α-helix connected to three antiparallel β-sheets, which is stabilized with three disulfide bridges (see figure 1).
Ctri9577 has low sequence similarity (<50%) with most other members of the α-KTx15 subfamily., placing it far away on the phylogenetic tree
A phylogenetic tree or phylogeny is a graphical representation which shows the evolutionary history between a set of species or taxa during a specific time.Felsenstein J. (2004). ''Inferring Phylogenies'' Sinauer Associates: Sunderland, MA. In ...
. Target
Ctri9577 is a toxin specific forvoltage-gated potassium channels
Voltage-gated potassium channels (VGKCs) are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized ce ...
, which functions both as a potent Kv1.3 channel-blocker and a gating modifier of Kv4.3 channels. The Kv1.3 channels are inhibited with an IC50 of 0.49 ± 0.45 nM. Ctri9577 also modifies the gating of Kv4.3 channels through binding with the S3b-S4 linker within the voltage-sensing domain of the channel, in which four residues are of importance: L275, V276, N280, and V288. Ctri9577’s inhibition of Kv4.3 channel currents is much less potent ( IC50-value of 1.34 ± 0.03 μM) than the block of Kv1.3 channels.
Mode of action
The inhibitory effect of Ctri9577 on Kv1.3 channels is voltage-independent. The blocking of the delayed rectifier Kv1.3 is expected to slow down the repolarization phase of theaction potential
An action potential (also known as a nerve impulse or "spike" when in a neuron) is a series of quick changes in voltage across a cell membrane. An action potential occurs when the membrane potential of a specific Cell (biology), cell rapidly ri ...
.
Ctri9577's effect on Kv4.3 gating occurs through:
* shifting activation to more positive potentials
* shifting steady-state inactivation curves to more positive potentials, and
* slower recovery from open-state inactivation.
As a result, Kv4.3 channels will be inhibited.
References
{{DEFAULTSORT:Ctri9577 Scorpion toxins Potassium channel blockers Ion channel toxins