Goniopora toxin

Goniopora toxin (GPT) is a polypeptide toxin from the marine Goniopora species coral.[1] Two toxins from this source have been identified, one acting on sodium channels and one acting on calcium channels.[2][3][4]

Chemistry

The toxin acting on Na+ channels has a molecular weight of 12 kDa and consists of 105 amino acids. The GPT that acts on Ca2+ channels has a molecular weight of 19 kDa; its structure is as of yet unknown.

Mode of action

The 12 kDa GPT inhibits the inactivation of Na+ channels. This results in a maintained open state of the channel and allows for more Na+ influx.[2][5][6] As a result, the action potential duration is prolonged. The maintained open state of sodium channels induces a longer-lasting action potential, which allows for persistent activation of calcium channels and more calcium influx.[2][5] The prolongation of the action potential and its subsequent positive inotropic effect can be influenced by stimulus frequency; at higher frequencies (1 Hz), the effects of GPT were suppressed.[2] Furthermore, the effects of GPT on the sodium channels depend on the membrane potential of the cell preceding GPT binding, suggesting that the effects of GPT are potential-dependent. Also, in the presence of GPT, sodium channels are activated in response to an unusually small depolarizing stimulus.[7] The 19 kDa GPT stimulates Ca2+ influx and its activity can be prevented in the presence of a calcium channel blocker.[1][4] This suggests that GPT directly activates Ca2+ channels or indirectly activates Ca2+ by influencing sodium currents.

GPT effects in different species

Frequency-dependent effects of GPT were studied on bullfrog atrial muscle.[2] Application of GPT on the muscle showed broadening of action potential duration and showed a positive inotropic effect. When the stimulus frequency was increased, the effects of GPT were considerably suppressed as opposed to low-frequency stimulation. Also, the action potential was prolonged when long intervals of stimulation (1-3 min), in the presence of GPT, were used. In addition, when the cell membrane was hyperpolarized, the effects of GPT also increased, suggesting a potential-dependent effect on GPT toxicity.

Various GPT concentrations (10 – 100 nM) were added to guinea-pig blood vessels, which induced a contraction of the thoracic aorta, portal vein, and mesenteric and femoral arteries via an action on the innervation of the vessels.[3]

In neuroblastoma cells, even a small depolarizing stimulus can cause activation of sodium channels in the presence of GPT.[8]

In the rabbit myocardium GPT enhances atrial contractility and induce arrhythmias at concentrations above 30 nM.[8] The action potential duration was irreversibly prolonged, but there was no effect on the amplitude of the action potential or an effect on the resting membrane potential.

In guinea-pig ventricular cells, the 12 kDa GPT prolonged the action potential by acting on sodium channels, again with no effect on action potential amplitude and the resting membrane potential.[9]

At a concentration of 1.7 µM, the 19 kDa GPT induced contraction of the guinea pig ileum. This contraction was inhibited by a calcium channel blocker.[4]

In cultured chick cardiac cells the 19 kDa GPT induced an activation of calcium influx.[4] The concentration that resulted in a half-maximum activation of calcium influx was 5.3 µM.

Toxicity and treatment

GPT is highly toxic, with a lethal dose found in mice of 0.3-0.5 mg/kg when the 12 kDa GPT was injected intraperitoneally.[6][8] Symptoms consist of hypersensitivity, paralysis of hind limbs, diarrhea, rigidity of the entire body, and GPT can lead to a blue or purple discoloration of the skin. Tetrodotoxin, a sodium channel blocker, can be administered to suppress the prolonged action potential. Ca2+-channel blockers (e.g. nitrendipine and desmethoxyverapamil) can be used to suppress the effects of the calcium channel toxin.[1][4][9]

References

  1. 1 2 3 Wu, C.H.; Narahashi, T. (1988). "Mechanism of Action of Novel Marine Neurotoxins on Ion Channels". Annu. Rev. Pharmacol. Toxicol. 28: 141–161.
  2. 1 2 3 4 5 Noda, M.; Muramatsu, I.; Fujiwara, M.; Ashida, K. (1985). "Effects of Goniopora Toxin on Bullfrog Atrial Muscle Are Frequency-dependent". Pharmacology. 330: 59–66.
  3. 1 2 Muramatsu, I.; Fujiwara, M.; Ikushima, S.; Ashida, K. (1980). "Effects of Goniopora Toxin on Guinea-Pig Blood Vessels". Pharmacology. 312: 193–197.
  4. 1 2 3 4 5 Qar, J.; Schweitz, H.; Schmid, A.; Lazdunski, M. (1986). "A Polypeptide Toxin From the Coral Goniopora: Purification and Action on Ca2+ Channels". FEBS Lett. 202 (2): 331–336.
  5. 1 2 Noda, M.; Muramatsu, I.; Fujiwara, M. (1984). "Effects of Goniopora Toxin on the Membrane Currents of Bullfrog Atrial Muscle". Arch. of Pharmacology. 327: 75–80.
  6. 1 2 Hashimoto, Y.; Ashida, K. (1973). "Screening of Toxic Corals and Isolation of A Toxic Polypeptide From Goniopora Spp". Publ. of the Seto Marine Biol. 20: 703–711.
  7. ↑ Gonoi, T. and B. Hille (1987). "Gating of Na channels. Inactivation modifiers discriminate among models." J Gen Physiol 89(2): 253-274.
  8. 1 2 3 Fujiwara, M.; Muramatsu, I.; Hidaka, H.; Ikushima, S.; Ashida, K. (1979). "Effects of Goniopora Toxin, a Polypeptide Isolated from Coral, on Electromechanical Properties of Rabbit Myocardium". J. of Pharmacol. and Exp. Therapeutics. 210 (2): 153–157.
  9. 1 2 Nishio, M.; Muramatsu, I.; Kigoshi, S.; Fujiwara, M. (1988). "Effects of Goniopora Toxin on the Action Potential and Membrane Currents of Guinea-Pig Single Ventricular Cells". Pharmacology. 337: 440–446.
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