Chemistry: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
- ↑ 1.0 1.1 1.2 Wu, C.H.; Narahashi, T. (1988). "Mechanism of Action of Novel Marine Neurotoxins on Ion Channels". Annu. Rev. Pharmacol. Toxicol. 28: 141–161. doi:10.1146/annurev.pa.28.040188.001041. PMID 2454608.
- ↑ 2.0 2.1 2.2 2.3 2.4 Noda, M.; Muramatsu, I.; Fujiwara, M.; Ashida, K. (1985). "Effects of Goniopora Toxin on Bullfrog Atrial Muscle Are Frequency-dependent". Pharmacology 330 (1): 59–66. doi:10.1007/BF00586710. PMID 2413371.
- ↑ 3.0 3.1 Muramatsu, I.; Fujiwara, M.; Ikushima, S.; Ashida, K. (1980). "Effects of Goniopora Toxin on Guinea-Pig Blood Vessels". Pharmacology 312 (2): 193–197. doi:10.1007/BF00569730. PMID 6250087.
- ↑ 4.0 4.1 4.2 4.3 4.4 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. doi:10.1016/0014-5793(86)80712-8. PMID 2424789.
- ↑ 5.0 5.1 Noda, M.; Muramatsu, I.; Fujiwara, M. (1984). "Effects of Goniopora Toxin on the Membrane Currents of Bullfrog Atrial Muscle". Naunyn-Schmiedeberg's Archives of Pharmacology 327 (1): 75–80. doi:10.1007/BF00504995. PMID 6092970.
- ↑ 6.0 6.1 Hashimoto, Y.; Ashida, K. (1973). "Screening of Toxic Corals and Isolation of A Toxic Polypeptide From Goniopora Spp". Publications of the Seto Marine Biological Laboratory 20: 703–711. doi:10.5134/175749.
- ↑ Gonoi, T.; Hille, B. (February 1987). "Gating of Na channels. Inactivation modifiers discriminate among models.". The Journal of General Physiology 89 (2): 253–74. doi:10.1085/jgp.89.2.253. PMID 2435840.
- ↑ 8.0 8.1 8.2 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". Journal of Pharmacology and Experimental Therapeutics 210 (2): 153–157. http://jpet.aspetjournals.org/content/210/2/153.
- ↑ 9.0 9.1 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 (4): 440–446. doi:10.1007/BF00169537. PMID 2457173.
 |  |
