Cangitoxin, also known as CGTX or CGX, is a toxin purified from the venom of the sea anemone ''

Bunodosoma ''Bunodosoma'' is a genus of sea anemones in the family Actiniidae. Species Species in the genus include: * ''Bunodosoma biscayense'' (Fischer, 1874) * ''Bunodosoma caissarum'' Corrêa in Belém, 1987 * ''Bunodosoma californicum'' Carlgren, ...

cangicum'', which most likely acts by prolonging the inactivation of

voltage-gated sodium channels Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the channel ...

(Na_V channels).

Sources

Cangitoxin is a

polypeptide 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 ...

isolated from 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 ...

of ''Bunodosoma cangicum'', a common sea anemone species found in the

intertidal zone The intertidal zone, also known as the foreshore, is the area above water level at low tide and underwater at high tide (in other words, the area within the tidal range). This area can include several types of habitats with various species ...

during low tides on the coastal reefs of the Brazilian seashore.

Chemistry

Structure

Cangitoxin belongs to the type 1 class sea anemone toxins, consisting of long polypeptides with short anti-parallel β–sheets and three disulfide bonds. Cangitoxin is a 4958 Da peptide, with the

primary structure Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthes ...

GVACRCDSDGPTVRGNSLSGTLWLTGGCPSGWHNCRGSGPFIGYCCKK and disulfide bonds Cys4-Cys45, Cys6-Cys35, and Cys28-Cys46. It contains 48 amino acid residues. Substitution of the 16th amino acid,

asparagine Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...

(N), into an

aspartic acid Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α- amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pr ...

(D) is named cangitoxin-II (CGTX-II). Cangitoxin-III (CGTX-III) contains in addition to the previous substitution, a replacement of the 14th amino acid,

arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the a ...

(R), into

histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the ...

(H).

Homology

Cangitoxin is to varying degrees homologous to the other sea anemone toxins. The most prominent is the homology to the type 1 class sea anemone toxins (85%). The homology of cangitoxin to the type 2 and 3 class sea anemone toxins is less, respectively 50% and 30%. The major neurotoxin BcIII (BcIII) isolated from ''

Bunodosoma caissarum ''Bunodosoma'' is a genus of sea anemones in the family Actiniidae. Species Species in the genus include: * '' Bunodosoma biscayense'' (Fischer, 1874) * '' Bunodosoma caissarum'' Corrêa in Belém, 1987 * '' Bunodosoma californicum'' Carlgren, ...

'' is homologous to cangitoxin. It has two homologous amino acid substitutions (S17T and S19T) and one non-homologous substitution (V13S). This makes it 94% identical and 98% homologous to cangitoxin.

Target and mode of action

Sea anemone toxins act on voltage-gated sodium channels ( Na_V1.1, Na_V1.2, Na_V1.4, Na_V1.5, Na_V1.6, Na_V1.7) and depending on their affinity to a specific

isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some iso ...

, they mainly act on cardiac or neuronal voltage-gated sodium channels. Sea anemone toxins act at the receptor site 3. On the basis of its sequence homology, cangitoxin most likely acts on the same receptor site of the previously mentioned sodium channels. Neurotoxin receptor site 3 is localized on the extracellular side of the IVS4 transmembrane segment. The S4 segments of sodium channels move outward when the membrane depolarizes. According to its sequence homology, it is likely that cangitoxin prolongs the inactivation of the voltage-gated sodium channels by binding on the external side of the plasma membrane, thereby preventing the outward movement of the IVS4 transmembrane segment. This blockage prevents the conformational change that is essential for inactivation. The prolongation of the inactivation has been demonstrated in experiments in which the effect of cangitoxin-II and –III on the Na_V1.1 channel was investigated.

Toxicity

Intrahippocampal injection of 8 µg of cangitoxin in rats has strong behavioral effects, leading to

akinesia Hypokinesia is one of the classifications of movement disorders, and refers to decreased bodily movement. Hypokinesia is characterized by a partial or complete loss of muscle movement due to a disruption in the basal ganglia. Hypokinesia is a sym ...

interchanging with facial automatisms and head

tremor A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, f ...

, salivation, rearing, jumping, barrel-rolling, wet dog shakes and forelimb clonic movements. In addition, convulsions occur which gradually increase in duration, leading to a

status epilepticus Status epilepticus (SE), or status seizure, is a single seizure lasting more than 5 minutes or 2 or more seizures within a 5-minute period without the person returning to normal between them. Previous definitions used a 30-minute time limit. The s ...

. The

electroencephalogram Electroencephalography (EEG) is a method to record an electrogram of the spontaneous electrical activity of the brain. The biosignals detected by EEG have been shown to represent the postsynaptic potentials of pyramidal neurons in the neocorte ...

shows

spike-and-wave Spike-and-wave is a pattern of the electroencephalogram (EEG) typically observed during epileptic seizures. A spike-and-wave discharge is a regular, symmetrical, generalized EEG pattern seen particularly during absence epilepsy, also known as ‘ ...

, which is typically seen during epileptic convulsions. Lower intrahippocampal doses of cangitoxin (2-4 µg) do not lead to either behavioral or EEG alterations in rats. Higher doses of cangitoxin (12-16 µg) induce severe tonic-clonic convulsions, leading to death.

References

{{reflist, 33em Ion channel toxins Sea anemone toxins