AmmTX3, produced by ''

Androctonus Fattail scorpion or fat-tailed scorpion is the common name given to scorpions of the genus ''Androctonus'', one of the most dangerous groups of scorpion species in the world.Hendrixson, B. E. 2006. Buthid scorpions of Saudi Arabia, with notes ...

mauretanicus'', is a

scorpion toxin Scorpion toxins are proteins found in the venom of scorpions. Their toxic effect may be mammal- or insect-specific and acts by binding with varying degrees of specificity to members of the Voltage-gated ion channel superfamily; specifically, volt ...

of the α-KTX15 subfamily. The toxin is known for its ability to act as a specific Kv4 channel blocker, and thereby reducing the A-type potassium current through this channel.

Etymology and source

AmmTX3 (α-KTX15.3) is a peptide that can be isolated from the venom of ''Androctonus mauretanicus''. ''Androctonus mauretanicus'' is a fat-tailed scorpion with its origins in North Africa.

Chemistry

AmmTX3 has a molecular mass of 3823.5 Da and consists of a single chain of 37 amino acid residues. These residues are cross-linked by three disulfide bridges. The toxin contains the dyad characteristic (K27 and Y36) that is found in pore-blocking potassium channel-specific toxins, and is therefore likely to act as a pore blocker. AmmTX3 is a member of the α-KTX15 subfamily. This subfamily currently exists of six very homologous peptides, originating from scorpion venom: Aa1, AaTX1, AaTX2, AmmTX3, BmTx3 and Discrepin. Toxins of the α-KTX15 subfamily all seem to have an effect on the A-type potassium current.

Target

AmmTX3 is a specific pore blocker of

Kv4.2 Potassium voltage-gated channel subfamily D member 2 is a protein that in humans is encoded by the ''KCND2'' gene. It contributes to the cardiac transient outward potassium current (Ito1), the main contributing current to the repolarizing phase ...

and

Kv4.3 Potassium voltage-gated channel subfamily D member 3 also known as Kv4.3 is a protein that in humans is encoded by the ''KCND3'' gene. It contributes to the cardiac transient outward potassium current (Ito1), the main contributing current to the r ...

channels of mice. This high-affinity blockade depends on the expression of dipeptidyl peptidase-like proteins (DPP) DPP6 and DPP10, which are proteins that co-assemble with the alpha-subunits of Kv4 channels. Besides its potent ability to block Kv4 channel, AmmTx3 also has a small blocking effect on

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 without alteration of the gating kinetics.

Mode of action

By blocking specifically the Kv4 channels, AmmTX3 reduces the A-type potassium current through these channels almost completely. A-type potassium currents can be generated by Kv1.4, Kv3.3, Kv3.4, all members of Kv4 and Erg3 channels. The influence of AmmTX3 on the overall A-type potassium currents hence depends on the specific channel types that mediate this current in the cell. For example, in the

solitary nucleus In the human brainstem, the solitary nucleus, also called nucleus of the solitary tract, nucleus solitarius, and nucleus tractus solitarii, (SN or NTS) is a series of purely sensory nuclei (clusters of nerve cell bodies) forming a vertical column ...

, the A-type potassium current is Kv4-mediated. Therefore, presence of AmmTX3 in the solitary nucleus cells blocks the A-type potassium current almost completely. Similar effects have been found in the

hippocampus The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, a ...

substantia nigra The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. ''Substantia nigra'' is Latin for "black substance", reflecting the fact that parts of the substantia nigra app ...

, and

cerebellum granule cell Cerebellar granule cells form the thick granular layer of the cerebellar cortex and are among the smallest neurons in the brain. (The term granule cell is used for several unrelated types of small neurons in various parts of the brain.) Cereb ...

s of rats and mice. While AmmTX3 nearly completely blocks the transient component of the A-type potassium current in cerebellar granular neurons at 0.5 μM, the sustained component of the current, which is thought to be Kv3.1 mediated, seems unaffected, in contrast to Aa1 and BmTX3. AmmTX3 is predominantly used in research setting, where it is often injected into specific brain areas to learn more about the role of Kv4 channels in those areas. For example, AmmTX3 possibly impairs the consolidation of spatial information and learning strategy through Kv4 channel inhibition, as found within rats in a radial-maze task. AmmTX3 also increases spontaneous pacemaking frequency in substantia nigra pars compacta dopaminergic neurons

Toxicity

The Ki of AmmTX3 was found to be approximately 131 nM when tested on striatal neurons in cell culture. AmmTX3 has a small blocking effect on hERG channels with an IC50 of 7.9 ± 1.4 μM.

References

{{reflist Ion channel toxins Scorpion toxins