Anthopleurin

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Anthopleurin is a toxin from the venom of the sea anemones Anthopleura xanthogrammica and Anthopleura elegantissima . These anemones use anthopleurin as a pheromone to quickly withdraw their tentacles in the presence of predators. Anthopleurin has four isoforms (Anthopleurin-A, -B, -C, and -Q). Their working mechanism is based on binding to sodium channels, which leads to increased excitation especially in cardiac myocytes. [1]

Contents

Function in sea anemones

Anthopleurin functions both as a toxin as well as a pheromone. When a predator approaches the anemone, their reaction is to withdraw their tentacles and oral disc. These are the preferred attack sites for predators, because the concentration of anthopleurin is the lowest in these sites. The body region of the sea-anemone that is exposed to the predator contains the highest concentration of anthopleurin. After consuming the sea-anemone, the predator travels through the water and actually helps to spread the anthopleurin. This functions as an alarm pheromone for the other anemones, so they can hide certain body parts and defend themselves. [2]

Sources

Anthopleura xanthogrammica (Giant green anemone) and Anthopleura elegantissima (Aggregating anemone) are named after the terrestrial anemone flower and are typically found along rocky, tidy shores in the Pacific Ocean.

Molecular structure

Anthopleurins are water-soluble proteins. They are built of four short strands of antiparallel beta-sheets, and contain three disulfide bridges. [2] [3]

IsoformAmino acids residuesMolecular weight (Dalton)Location of disulfide bridges
Anthopleurin A4951384–46, 6–36, 29–47
Anthopleurin B4952744–46, 6–36, 29–47
Anthopleurin C4748844–44, 6–34, 27–45
Anthopleurin Q404840unknown
IsoformSequencemolecular formula
AP-AGVSCLCDSDG-PSVRGNTLSG-TLWLYPSGCP SGWHNCKAHG-PTIGWCCKQC220H326N64O67S6
AP-BGVPCLCDSDG-PRPRGNTLSG-ILWFYPSGCP-SGWHNCKAHG-PNIGWCCKKC231H344N68O63S6
AP-CGVPCLCDSDG-PSVRGNTLSG-ILWLAGCPSG-WHNCKAHGPT-IGWCCKQC210H316N62O61S6
AP-Qunknownunknown

Mode of action

Anthopleurins bind to the extracellular site-3 of mammalian sodium channels. Anthopleurins can affect cardiac myocytes by binding to the cardiac isoform of the sodium channel, RT4-B. Anthopleurins slow down inactivation of the sodium channels [4] As a result, they can have positive inotropic effects on the whole heart. [5] Pre-treatment with AP-Q has an effect on hepatocytes in CCl4-induced acute liver injury, decreasing the activity of aspartate transaminase (AST) and alanine transaminase (ALT) in the liver. [6]

Potency

All different forms of anthopleurin are potent toxins. Anthopleurin A and C show effect at concentrations of 50 nM, Anthopleurin B at 3 nM and AP-Q at 30 nM. [7]

Mechanism of toxin action

Anthopleurin can bind to the extracellular site of voltage-gated sodium channels. This results in slower inactivation, which has a positive inotropic effect on the heart. Anthopleurin has no effect on heart rate and blood pressure when given in concentrations of normal range. When the concentration of anthopleurin gets too high, arrhythmia of the heart can occur and this can cause serious damage or even death. [1] Intoxication in humans is very rare.

Therapeutic implications

Cardiac therapeutic implications

Since AP is known to have an excitatory effect on cardiac muscle contractility at very low concentrations, without interfering with heart rate and blood pressure, it has been suggested to be useful as a possible treatment for patients with heart failure. Digoxin (purified cardiac glycoside) has more side-effects and is less potent than AP (which is 200 times more potent in the case of AP-A and AP-C, while AP-B is even more potent). AP-Q is quite similar to vesnarinone, a quinolinone derivative, a medicine that can be given to patients with chronic heart failure. Only lower doses of both AP-Q and vesnarinone have beneficial effects without raising blood pressure or heart rhythm. There is a narrow dose range in which the contractility is improved but also arrhythmias could be induced. AP itself cannot be used for therapeutic admission, because the stability of the molecule after oral transmission is too low and an immunological reaction might occur since the molecule is unfamiliar to the body. However, it may be possible to modify its structure using biological engineering. [5] [8]

Studies have also been performed to investigate the effects of AP-Q in acute liver injury. Given in low doses (3.5–7 microgram/kg) AST and ALT are decreased, whereas high doses of AP-Q (14 microgram) increase these liver enzyme values. AP-Q also increases the delayed outward potassium current thereby increasing the outflow of potassium ions from hepatocytes. This causes a hyperpolarization of its membrane potential. This hyperpolarizing effect could lead to increased uptake of substrates that help in restoring the cellular ATP levels. [6]

Related Research Articles

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BcIII

BcIII is a polypeptide sea anemone neurotoxin isolated from Bunodosoma caissarum. It targets the site 3 of voltage-gated sodium channels, thus mainly prolonging the inactivation time course of the channel.

ATX-II, also known as neurotoxin 2, Av2, Anemonia viridis toxin 2 or δ-AITX-Avd1c, is a neurotoxin derived from the venom of the sea anemone Anemonia sulcata. ATX-II slows down the inactivation of different voltage-gated sodium channels, including Nav1.1 and Nav1.2, thus prolonging action potentials.

APETx1 is a peptide toxin from the venom of the sea anemone Anthopleura elegantissima. The toxin acts as a gating modifier on the human ether-à-go-go-related gene (hERG) channel, a type of voltage-gated potassium channel, and as a blocker of voltage-gated sodium channels, including Nav1.2 and Nav1.8.

Goniopora toxin (GPT) is a polypeptide toxin from the marine Goniopora species coral. Two toxins from this source have been identified, one acting on sodium channels and one acting on calcium channels.

References

  1. 1 2 Moran Y, Gordon D, Gurevitz M. "Sea anemone toxins affecting voltage-gated sodium channels—molecular and evolutionary features". Toxicon 2009, 54(8): 1089–1101.
  2. 1 2 Howe NR, Sheikh YM. "Anthopleurin: a sea anemone alarm pheromone". Science 1975, 189(4200): 386–8.
  3. ↑ Pallaghy PK, Scanlon MJ, Monks SA, Norton RS. "Three-dimensional structure in solution of the polypeptide cardiac stimulant anthopleurin-A". Biochemistry. 1995 Mar 21;34(11):3782–94.
  4. ↑ Paramjit K. Khera et al, "Multiple Cationic Residues of Anthopleurin B that Determine High Affinity and Channel Isoform Discrimination". Biochemistry 1995,34, 8533–8541.
  5. 1 2 Zhou J, Fu L et al. "Effects of anthopleurin-Q on myocardial hypertrophy in rats and physiologic properties of isolated atria in guinea pigs". Acta Pharmacol Sin 2002, 23(10): 924–929
  6. 1 2 Zhou H, Wang F, Zhang K, Cheng L, Zhou J, Fu L, Yao W. "Electrophysiological effects of anthopleurin-Q on rat hepatocytes". World J Gastroenterol 2004, 10(1):96–99
  7. ↑ T.R. Norton, Y. Ohizumi & S. Shibata. "Excitatory effect of a new polypeptide Anthopleurin-B from sea anemone on the guinea-pig vas deferens". Br. J. Pharmac. (1981), 74, 23–28
  8. ↑ Bailey P, Wilce J. "Venom as a source of useful biologically active molecules". Emergency Medicine 2001, 13: 28–36
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