Phrixotoxins are

peptide 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. ...

toxins A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. Toxins occur especially as a protein or conjugated protein. The term toxin was first used by organic chemist Ludwig Brieger (1849 ...

derived from the venom of the Chilean copper

tarantula Tarantulas comprise a group of large and often hairy spiders of the family Theraphosidae. , 1,040 species have been identified, with 156 genera. The term "tarantula" is usually used to describe members of the family Theraphosidae, although ...

''Phrixotrichus auratus'', also named ''Paraphysa scrofa''. Phrixotoxin-1 and -2 block A-type

voltage-gated potassium channel 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 c ...

s; phrixotoxin-3 blocks

voltage-gated sodium channel 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 ...

s. Similar toxins are found in other species, for instance the Chilean rose tarantula.

Sources

Phrixotoxins are purified from the venom of the spider ''Phrixotrichus auratus'' , but they can also be produced by chemical

peptide synthesis In organic chemistry, peptide synthesis is the production of peptides, compounds where multiple amino acids are linked via amide bonds, also known as peptide bonds. Peptides are chemically synthesized by the condensation reaction of the carboxy ...

Structure

There are three different phrixotoxins: *Phrixotoxin-1 (PaTx1) – which is composed of 29 amino acids *Phrixotoxin-2 (PaTx2) – which is composed of 31 amino acids *Phrixotoxin-3 (PaurTx3 or Beta-theraphotoxin-Ps1a) – which is composed of 34 amino acids Phrixoseq

PaTx1 is 83.3% identical to PATx2, differing only by two acidic residues. Phrixotoxin-1 and -2 are similar to heteropodatoxin, which also has a blocking activity on Kv4.2 channels . Phrixotoxin-1, -2 and -3 contain an

Inhibitor Cystine Knot An inhibitor cystine knot (aka ICK or Knottin) is a protein structural motif containing three disulfide bridges. Knottins are one of three folds in the cystine knot motif; the other closely related knots are the Growth Factor Cystine Knot (GFCK) ...

(ICK) motif, and thus belong to the ICK peptide family.

Target

Phrixotoxin-1 and -2 bind to A-type, transient, voltage-gated potassium channels, near the S3 and S4 segments, where they negatively affect transmembrane movement of the voltage sensing domain in response to depolarizing voltages. They bind preferentially to the closed or inactivated state of Kv4.2 and Kv4.3 channels. Phrixotoxin-3 (PaurTx3) inhibits several voltage gated sodium channel subtypes (Nav1.1/SCN1A, Nav1.2/SCN2A, Nav1.4/SCN4A, Nav1.5/SCN5A, and Nav1.8/SCN10A) .

Mode of action

Phrixotoxins 1 and 2 specifically block Kv4.2 and Kv4.3 channels by altering the voltage-dependent gating properties of these channels. Inhibition results from a shift of the conductance-voltage relation and steady-state inactivation properties to more depolarized potentials. These toxins also change Kv4.2 and Kv4.3 kinetics of activation and inactivation by a concentration-dependent increase of the time-to-peak current and time constant of current inactivation . Phrixotoxin-3 modulates voltage-gated sodium channels by causing a depolarizing shift in gating kinetics and by blocking the inward component of sodium current, thus preventing the channels from opening to a moderate depolarization, resulting in a reduced firing rate of the neurons .

Toxicity

Phrixotoxin-1

Mice that are injected with phrixotoxin-1 can experience numerous, transient, adverse cardiac reactions, such as premature ventricular beats,

ventricular tachycardia Ventricular tachycardia (V-tach or VT) is a fast heart rate arising from the lower chambers of the heart. Although a few seconds of VT may not result in permanent problems, longer periods are dangerous; and multiple episodes over a short perio ...

, and atrio-ventricular blocks. Neurological effects observed are motor impairment and

convulsions A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is sometimes used as a ...

. These effects are seen following both intravenous and intracisternal injection, making it likely that phrixotoxin-1 crosses the blood brain barrier .

Phrixotoxin-3

Injection of this venom into mice causes immediate general

ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of t ...

, lack to response stimuli and semi-

paralysis Paralysis (also known as plegia) is a loss of motor function in one or more muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory damage. In the United States, roughly 1 in 5 ...

. Inability to stand and breathing reduction occurs within minutes.

Flaccid paralysis Flaccid paralysis is a neurological condition characterized by weakness or paralysis and reduced muscle tone without other obvious cause (e.g., trauma). This abnormal condition may be caused by disease or by trauma affecting the nerves associat ...

and slowing of breathing eventually cause death .

References

{{cite journal , vauthors=Bosmans F, Rash L, Zhu S, Diochot S, Lazdunski M, Escoubas P, Tytgat J , title=Four novel tarantula toxins as selective modulators of voltage-gated sodium channel subtypes , journal=Mol Pharmacol , volume=69 , issue=2 , pages=419–29 , year=2006 , pmid=16267209 , doi=10.1124/mol.105.015941, s2cid=10093118 Ion channel toxins Neurotoxins