Verrucotoxin (VTX) is a lethal venom produced by the dorsal fins of ''

Synanceia verrucosa ''Synanceia verrucosa'', the reef stonefish or simply stonefish, is a species of Venomous fish, venomous, marine ray-finned fish, belonging to the subfamily Synanceiinae which is Taxonomy (biology), classified as being within the Family (biology) ...

''. This species of reef stonefish is connected to the family ''

Synanceiidae Synanceiinae is a subfamily of Venom, venomous ray-finned fishes, waspfishes, which is classification of life, classified as part of the family Scorpaenidae, the scorpionfishes and their relatives. These fishes are found in the Indo-Pacific ocean ...

''. The venom of this species of stonefish is a

tetrameric A tetramer () (''tetra-'', "four" + '' -mer'', "parts") is an oligomer formed from four monomers or subunits. The associated property is called ''tetramery''. An example from inorganic chemistry is titanium methoxide with the empirical formula Ti ...

glycoprotein Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...

with

cardiovascular In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart a ...

and

cytolytic Cytolysis, or osmotic lysis, occurs when a cell bursts due to an osmotic imbalance that has caused excess water to diffuse into the cell. Water can enter the cell by diffusion through the cell membrane or through selective membrane channels ...

effects.

Structure

The structure of verrucotoxin is a

tetrameric protein A tetrameric protein is a protein with a quaternary structure of four subunits (tetrameric). Homotetramers have four identical subunits (such as glutathione S-transferase), and heterotetramers are complexes of different subunits. A tetramer ...

with a molecular weight of 322 KDa; the protein consists of two parts of an alpha subunit (83 KDa) and two parts of a beta subunit (78 KDa). Verrucotoxin shares a total of 96% homology to the closely related venom stonustoxin beta subunit. Stonustoxin is the venom produced from ''

Synanceia horrida ''Synanceia horrida'', the estuarine stonefish, hollow-cheek stonefish, horrid stonefish, rough stonefish or true stonefish, is a species of venomous, marine ray-finned fish, a stonefish belonging to the subfamily Synanceiinae which is classified ...

''.

Function and mechanism

Verrucotoxin has been studied to interact with both calcium ion channels and potassium ATP channels. The calcium ion channel is modulated by the activation of the β-adrenoceptors when verrucotoxin binds. There are three subunits of β-adrenoceptors, β1, β2, and β3, but only β2-adrenoceptors are responsible for the activation of the

cyclic adenosine monophosphate Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger, or cellular signal occurring within cells, that is important in many biological processes. cAMP is a derivative of adenosine tri ...

(cAMP)-

protein kinase A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them ( phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a f ...

(PKA) pathway. The cAMP will phosphorylate muscle regulatory proteins and modulate intercellular calcium concentrations. It is through this method that verrucotoxin operates the concentrations of calcium in the cell. Verrucotoxin is a concentration-dependent toxin to the concentration of calcium ions; the presence of verrucotoxin can increase the calcium concentration three times the standard intercellular concentration. Additionally, verrucotoxin has been observed to cause a reversible prolonged action potential duration with zero change in resting membrane potential from ventricular myocytes in guinea pigs. The second method verrucotoxin disrupts cells are through

potassium ion 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 c ...

s, particularly the potassium adenosine triphosphate (KATP) pathway. The potassium ATP channel operates by pumping potassium ions out of the intercellular membrane.{{Cite journal, last1=Tinker, first1=Andrew, last2=Aziz, first2=Qadeer, last3=Thomas, first3=Alison, date=January 2014, title=The role of ATP-sensitive potassium channels in cellular function and protection in the cardiovascular system, journal=British Journal of Pharmacology, volume=171, issue=1, pages=12–23, doi=10.1111/bph.12407, issn=0007-1188, pmc=3874693, pmid=24102106 It’s capable of doing so by

phosphorylating In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writt ...

the channel with

adenosine triphosphate Adenosine triphosphate (ATP) is a nucleoside triphosphate that provides energy to drive and support many processes in living cell (biology), cells, such as muscle contraction, nerve impulse propagation, and chemical synthesis. Found in all known ...

(ATP). Verrucotoxin is able to inhibit the operation of the potassium ATP through the activation of muscarinic M3 receptor-

protein kinase C In cell biology, protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and t ...

(PKC). It is the activation of the PKC that will inhibit the potassium ion channel. The PKC is presumably phosphorylating the KATP channel instead of ATP.

Adverse effects

The stonefish, ''

'', has a diverse set of toxins that disrupts basic human ability. When injected with the toxins found in the dorsal fins of the fish, individuals will suffer from skeletal muscle paralysis, extreme pain,

seizure A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

convulsion 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 often used as a synony ...

respiratory arrest Respiratory arrest is a serious medical condition caused by apnea or respiratory dysfunction severe enough that it will not sustain the body (such as agonal breathing). Prolonged apnea refers to a patient who has stopped breathing for a long period ...

, and damage to the

cardiovascular system In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart a ...

. Verrucotoxin has been studied to be the cause of cardiovascular system damage, convulsions, seizures, and paralysis. For the cardiovascular system damage, it is caused by the sudden change in the intercellular calcium concentration leading to

arrhythmia Arrhythmias, also known as cardiac arrhythmias, are irregularities in the cardiac cycle, heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – ab ...

. The direct cause of seizures, convulsions, and paralysis are still being investigated.

References

Ichthyotoxins Potassium channel blockers Calcium channel openers Glycoproteins