The Action of Naturally Occurring Toxins and Medicines

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Table of Contents

Neurotransmission inhibitors
Hypersensitivity and allergic reactions
Modulators of G-protein mediated reactions
Parasympathetic nervous system agonists and antagonists
Enzyme modulating agents
Reference List

The listed compounds are grouped based on their action:

Neurotransmission inhibitors

Number of toxins target sympathetic and parasympathetic synapses and nerve muscle junctions with acetylcholine neurotransmitter released from presynaptic nerve terminals. Acetylcholine diffuses through synaptic clefts and bind to specific nicotinic or cholinergic postsynaptic receptors, and opens the acetylcholine (ligand) gated Na⁺ channels to accomplish rapid intake of sodium and depolarization of nerve fiber (Tortora & Grabowski 2003, p. 397, 575). Equivalent efflux of intracellular K⁺ through K⁺ channels re-polarizes the nerves. Depending on nature of toxin, the action could be pre- or postsynaptic (Karalliedde 1995).

Cobratoxins and α-Bungarotixin – According to Marshall (1981), α-Bungarotixin reversibly blocks the postsynaptic action potential, particularly depolarization. Immunocytochemistry with acetylcholine receptor antibody reveals that toxin binds towards the proximal end of postganglionic neurons and prevents acetylcholine binding. Cholinergic agonists compete with α-Bungarotixin and resume conduction of nerve impulse.

Kumar et al. (1999) categorized cobra neurotoxins, of which α-Cobratoxin’s action resembles to that of α-Bungarotixin but its binding is more revertible. The toxin displays characteristic three “finger” domains interacting with acetylcholine receptors. The crystal structure of α-Cobratoxin-acetylcholine receptor complex was characterized by Bourne et al. (2005). The three “fingered” peptide binds to pentameric acetylcholine receptor and brings about conformational changes.

Tetrodotoxin – According to Cohen et al. (1981) and Noda et al. (1986), the Puffer fish poison blocks the tetra-isodomain Na⁺ channels and prevents influx of Na⁺ even after acetylcholine binding. Tetrodotoxin is much larger than Na⁺ but yet it competes with hydrated Na⁺, and like a cork fits over the channel. The toxin’s guanidino group bonds with carboxylate groups of proximal channel proteins. The Na⁺ channel is a voltage two-gated system, where repeated depolarization regulates the gating current and Na⁺ movements, which does not seem to be affected by Tetrodotoxin. In Puffer fish, Na⁺ channels, due to one amino acid mutation, loose affinity to their own toxin.

Dendrotoxins – The α-, β-, γ- and δ-variants of Dendrotoxins from black mamba are neuronal K⁺ channel blockers, exhibiting selectivity towards multiple channel subtypes. According to Scott et al. (1994), Dendrotoxin sensitive K⁺ channels are comprised of trans-membrane α and internal β subunits, the later shows remarkable extent of divergence. This versatility explains tissue specificity of toxin’s actions and insensitivity towards the snake receptors. Dendrotoxins also exert unique activity of serine proteinase inhibitors, with no apparent role in K⁺ channel binding. The overall manifestation of K⁺ channel blockers is the delayed re-polarization and eventual delayed depolarization, thereby slowing down the conductance.

Charybdotoxin – This scorpion venom toxin affects localized muscle contraction. It is a strong antagonist of open or close form of sarcolemal Ca²⁺-activated K⁺ channels. In skeletal muscles, Ca²⁺ is the signal molecule triggering K⁺ expulsion after intake of Ca²⁺ that follows depolarization from Na⁺ uptake. The toxin binding is a physical plugging of the pores rather than any stable interaction (MacKinnon & Miller 1988). Internal K⁺ dissociates the positively charged toxin by electrostatic expulsion from channel mouth and relieves the inhibition. This effect is dependent on depolarization. Excess K⁺ accumulation and occlusion of toxin seems to be the defense mechanism for scorpion. Though the action is K⁺ channel blockade, unlike Dendrotoxin’s neuronal action, Charybdotoxin affects muscles.

Hypersensitivity and allergic reactions

Mast Cell Degranulating Peptide (MCDP) – This is cytolytic peptide degranulating skin mast cells, which releases histamine causing reddishness, swelling and localized pain. The severe toxic manifestation is due to allergen induce release of histamines, leukotrienes, prostaglandins, chemotactic factors etc. that affects dermal, gastrointestinal and respiratory systems, and airway obstruction and anaphylactic shock are the principle cause of death (Palma, 2006).

Modulators of G-protein mediated reactions

Cholera toxin – It is composed of A and B subunits. While B subunit recognizes ganglioside receptors of the intestinal villi cells, A subunit manifests toxicity. The toxin activates the GTP-dependent regulatory protein G_s, which reacts with NAD to derive ADP-ribose-G_s, a reaction accelerated by Cholera toxin. The activated G_s reacts with GTP, and this complex activates adenylate cyclase to produce cAMP. Another cellular target of Cholera toxin is inhibition of guanosine triphosphatase activity and resultantly reduced GTP hydrolysis (Cassel & Selinger, 1977), which further activates adenylate cyclase reaction. cAMP activates the protein kinases, and by downstream regulation, decreases the absorption of intestinal Na⁺ and Cl^–. Another signal transduction pathway involving phosphatidylinositol specific phospholipase C is also accelerated, which triggers Ca²⁺ transport and prevents NaCl intake.

Pertussis toxin – It is composed of S1, S2, S3, 2xS4 and S5 subunits. The most common response of the toxin is wooping cough. Unlike Cholera toxin, the S1 component of the toxin stimulates ADP-ribosylation of G-proteins G_i, G_o, transducin etc. (West et al. 1985). The activated transducin reacts with retinal GTP and affects the coupling proteins of visual transduction in rods. The G-proteins also mediate activation of adenylate cyclase and increase cAMP, though the pathway is different from Cholera toxin. Cholera toxin also ribosylates transducin, but its sites are different from Pertussis toxin. Another function of the toxin (S2, S3) is adherence to ciliated tracheal epithelial cells and phagocytes using lactosylceramide glycolipid receptors. This eventually evokes hypersensitive response leading to wooping cough.

Parasympathetic nervous system agonists and antagonists

In sympathetic and parasympathetic nervous systems acetylcholine is the preganglionic neurotransmitter. The postganglionic parasympathetic neurons and sympathetic neurons intervening sweat glands also employ acetylcholine. The acetylcholine receptors are of two types: nicotinic and muscarinic. The ion channel coupled nicotinic receptors exist in ganglia and skeletal muscle motor end plate. The heterotrimeric G-protein coupled muscarinic receptors exist on those organs where postganglionic nerve endings release acetylcholine, such as gastric mucosa, pericardium smooth muscles and glands.

Nicotine and Muscarine – Hösli et al. (1988) described that Muscarine from fungus Amanita muscaria is a muscarinic parasympathomimetic agonists stimulating cholinergic receptors in postganglionic parasympathetic neurons. Notwithstanding, Muscarine has no practical therapeutic value.

Nicotine serves as both agonist and antagonist at different concentrations. As antagonist, it competes with nicotinic but not muscarinic acetylcholine receptors. Excess of nicotine is dangerous for CNS and to avert this problem, acetylcholine is therapeutically applied to replace nicotine.

Atropine and Tubocurarine – These are cholinergic antagonists. Atropine, an alkaloid from Atropa belladonna, is a parasympatholytic acetylcholine mimicking agent, blocking the muscarinic and neuromuscular cholinergic receptors. Atropine has widespread therapeutic applications in inhibition of bronchial and gastric secretions, relaxation of bronchial and pupillary sphincter smooth muscle, cardioacceleration and CNS-modification. Ambache and Edwards (1951) highlighted the effect of atropine on reversal of nicotine’s effect on vagus-stomach nerve endings. Vagus is considered to be linked with two distinct sets of postganglionic neurons, one cholinergic stimulatory motor and the other adrenergic inhibitory. The nicotine stimulation prevails on the cholinergic postganglionic nerve endings, which is reverted by atropine without any impact on the adrenergic nerve endings. This gives a way to use atropine as a therapeutic drug for rehabilitation of nicotine abusive patients.

Tubocurarine is a nicotinic parasympatholytic antagonist mainly affecting the neuromuscular junctions without influencing the muscarinic cholinergic nerve endings. It is used as therapeutic agent for muscle relaxant during surgery, despite side effects like histamine release, hypotension and at high doses respiratory paralysis. In an investigation by Beranek and Vyskocil (1967), the action of atropine and tubocurarine on diaphragm was compared and it was concluded that these antagonists affects respectively the muscarinic and nicotinic acetylcholine receptors.

Enzyme modulating agents

Several natural products interfere with cellular energization associated ion transport and cytoskeleton integrity.

Ouabain and Digoxin – Cardiac glycosides stimulate the force of heart contraction by positive inotropic action that helps the patients with heart failure. The compounds have sugar and steroidal moieties and the later is the effective drug (Desai, 2000; Ling & Palmer, 1972). These agents retain sarcomeric Ca²⁺, enabling the contraction process to be effective and prolonged. Upon depolarization, there is an influx of Na⁺ which triggers entry of Ca²⁺, and elevated intracellular Ca²⁺expels K⁺. Such Na⁺/ K⁺ exchange requires activity of Na⁺-K⁺ ATPase. Glycosides inhibit this ATPase and lead to retention of intracellular Ca²⁺which maintains contraction. In pharmacokinetics experiments Digoxin, due to better absorption and half life, was found to be more effective drug than Ouabain.

Okadaic acid – The paralytic shellfish poison, Okadaic acid, is a strong inhibitor of serine/threonine protein phosphatases 1 and 2A (Gehringer, 2004) and influence cellular protein phosphorylation, especially in hepatocytes. The consequence of the inhibition is two fold: increased cellular proliferation and apoptosis. The cytoskeleton proteins undergo regular ATP-kinase dependent phosphorylation and phosphatases dependent dephosphorylation. Okadaic acid induces protein hyperphosphorylation, leading to changes in microtubule and microfilament functions. Apoptosis and oxidative stress lead to overall degradation of nucleic acids and lipids. Although Okadaic acid is not a drug, once its receptors are known it can be used for apoptotic destruction of cancerous cells.

To conclude, several natural products exhibit delicately balanced beneficial and harmful effects for humans. It would be necessary to understand the unique protective mechanisms in producing organisms so as to find immediate treatments for the poisoning. Moreover, it would be necessary to get insight into the mode of action so that their chemical structures can be modified for therapeutic applications.

Reference List

Ambache, N. & Edwards, J. 1951, ‘Reversal of nicotine action on the intestine by atropine’, British Journal of Pharmacology, vol. 6, pp. 311-317.

Beranek, R. & Vyskocil, F. 1967, ’The action of Tubocurarine and Atropine on the normal and denervated eat diaphragm’, Journal of Physiology, vol. 188, pp. 53-66.

Bourne, Y., Talley, T.T., Hansen, S.B., Taylor, P. & Marchot, P. 2005, ‘Crystal structure of a Cbtx–AChBP complex reveals essential interactions between snake α-neurotoxins and nicotinic receptors’, The EMBO Journal, vol. 24, pp. 1512–1522.

Cassel, D. & Selinger, Z. 1977, ‘Mechanism of adenylate cyclase activation by Cholera toxin: Inhibition of GTP hydrolysis at the regulatory site’, Proceedings of the National Academy of Sciences USA, vol. 74, no. 8, pp. 3307-3311.

Cohen, C.J., Bean, B.P., Colatsky, T.J. & Tsein, R.W. 1981, ‘Tetrodotoxin Block of Sodium Channels in Rabbit Purkinje Fibers’, Journal of General Physiology, vol. 78, pp. 383-411.

Desai, U.R. 2000, ’Cardiac Glycosides’, Web.

Gehringer, M.M. 2004, ‚Microcystin-LR and okadaic acid induced cellular effects: a dualistic response’, FEBS Letters, vol. 557, pp. 1-8.

Hösli, L., Hösli, E., Briotta, G.D., Quadri, L. & Heuss, L. 1988, ’Action of acetylcholine, muscarine, nicotine and antagonists on the membrane potential of astrocytes in cultured rat brainstem and spinal cord’, Neuroscience Letters, vol. 92, no. 2, pp. 165-170.

Karalliedde, L. 1995, ‘Animal toxins’, British Journal of Anaesthesia, vol. 74, pp. 319-327.

Kumar, T.K.S., Pandian, S.T.K., Jayaraman, G., Peng, H-J. & Yu, C. 1999,‘Understanding the Structure, Function and Folding of Cobra Toxins’, Proceedings of National Science Council. ROC(A), vol. 23, no. 1, pp. 1-19.

Ling, G.N. & Palmer, L.G. 1972, ‘Studies on ion permeability: IV. The mechanism of Ouabain action on the Na⁺-ion efflux in frog muscles’, Physiology, Chemistry & Physics, vol. 4, pp. 517-525.

MacKinnon, R. & Miller, C. 1988, ‘Mechanism of Charybdotoxin Block of the High-Conductance, Ca²⁺-activated K⁺ Channel’, Journal of General Physiology, vol. 91, pp. 335-349.

Marshall, L.M. 1981, ‘Synaptic localization of α-bungarotoxin binding which blocks nicotinic transmission at frog sympathetic neurons’, Proceedings of the National Academy of Sciences USA, vol. 78, no. 3, pp. 1948-1952.

Noda, M., Ikeda, T., Kayono, T., Suzuki, H., Takeshima, T., Kurasaki, M., Takahashi, H. & Numa, S. 1986, ‘Existence of distinct sodium channel messenger RNAs in rat brain’, Nature, vol. 320, pp. 188-192.

Palma, M.S. 2006, ‘Insect Venom Peptides’, in A.J. Kastin (ed.) Handbook of biologically active peptides, Academic Press, Burlington, San Diego, pp. 389-396.

Scott, V.E.S., Rettig, J., Parcej, D.N., Keen, J.N., Pongs, J.B.C.O. & Dolly, J.O. 1994, ‘Primary structure of a 13 subunit of α-dendrotoxin-sensitive K⁺channels from bovine brain’, Proceedings of the National Academy of Sciences USA, vol. 91, pp. 1637-1641.

Tortora, G.J. & Grabowski, S.R. 2003, Principles of Anatomy and Physiology, John Wiley & Sons, Inc., New York.

West, Jr., R.E., Moss, J., Vaughan, M., Lius, T. & Liug, T-Y. 1985, ‘Pertussis Toxin-catalyzed ADP-ribosylation of Transducin’, The Journal of Biological Chemistry, vol. 260, no. 27, pp. 14428-14430.

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