Peptide Neurotoxins from Fish-Hunting Cone Snails

Abstract

To paralyze their more agile prey, the venomous fish-hunting cone snails (Conus) have developed a potent biochemical strategy. They produce several classes of toxic peptides (conotoxins) that attack a series of successive physiological targets in the neuromuscular system of the fish. The peptides include presynaptic omega-conotoxins that prevent the voltage-activated entry of calcium into the nerve terminal and release of acetylcholine, postsynaptic alpha-conotoxins that inhibit the acetylcholine receptor, and muscle sodium channel inhibitors, the mu-conotoxins, which directly abolish muscle action potentials. These distinct peptide toxins share several common features: they are relatively small (13 to 29 amino acids), are highly cross-linked by disulfide bonds, and strongly basic. The fact that they inhibit sequential steps in neuromuscular transmission suggests that their action is synergistic rather than additive. Five new omega-conotoxins that block presynaptic calcium channels are described. They vary in their activity against different vertebrate classes, and also in their actions against different synapses from the same animal. There are susceptible forms of the target molecule in peripheral synapses of fish and amphibians, but those of mice are resistant. However, the mammalian central nervous system is clearly affected, and these toxins are thus of potential significance for investigating the presynaptic calcium channels.

P-type Ca2+ channels mediate excitatory and inhibitory synaptic transmitter release in crayfish muscle.

“…In contrast, both catecholamine and substance P released from bovine chromaffm cells and rat dorsal root ganglia neurons, respectively, are strongly inhibited by DHPs (16)(17)(18), suggesting a major participation of the L-type VDCC. However, while mammalian neuromuscular transmission is insensitive to either w-CgTX or DHPs (19)(20)(21), evoked synaptic transmission in squid giant synapse (3) and mammalian neuromuscular system (22) has been found to be inhibited by FTX and by its synthetic arginine-polyamine (spermidine) analogue (sFTX) (22,23), consistent with a key involvement of the P-type VDCC. Moreover, K+-evoked Ca2+ uptake and transmitter release in mammalian brain synaptosomes were only partially sensitive to w-CgTX and DHPs (24,25) but were inhibited by FTX (22) and w-Aga-IVA (26), indicating that the P-type VDCC mediates evoked transmitter release from many mammalian central synapses.…”

Evaluation of the bioactivities of water-soluble extracts from twelve deep-sea jellyfish species

“…For example, an anticancer drug Eribulin Ò [34] was developed from a cytotoxin halichondorin B isolated from a sponge [35]. An intractable pain reliever Prialt Ò was developed from x-conotoxin MVIIA from the marine Conus snail [36]. Furthermore, Yondelis Ò for treatment of sarcoma was also discovered as the potent cytotoxin ecteinascidin 743 from a Caribbean tunicate [37].…”

Calciseptine, a peptide isolated from black mamba venom, is a specific blocker of the L-type calcium channel.

“…This channel (or one subtype of N-type Ca2+ channel) is blocked by a natural polypeptide toxin isolated from Conus geographus and called c-conotoxin (9,14). This toxin thereby inhibits neurotransmitter secretion (13,15).…”