Conotoxin
Encyclopedia
A conotoxin is one of a group of neurotoxic
peptide
s isolated from the venom of the marine cone snail
, genus Conus
.
Conotoxins, which are peptides consisting of 10 to 30 amino acid
residues, typically have one or more disulfide bond
s. Conotoxins have a variety of mechanisms of actions, most of which have not been determined. However it appears that many of these peptides modulate the activity of ion channel
s.
Over the last few decades conotoxins have been subject of pharmacological interest.
channels, preferentially those of skeletal muscle
, and are useful probes for investigating voltage-dependent sodium channels of excitable tissue
s.
Different subtypes of voltage-gated sodium channels are found in different tissues in mammals, eg., in muscle and brain, and studies have been carried out to determine the sensitivity and specificity of the mu-conotoxins for the different isoforms.
Neurotoxicity
Neurotoxicity occurs when the exposure to natural or artificial toxic substances, which are called neurotoxins, alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue. This can eventually disrupt or even kill neurons, key cells that transmit and process...
peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
s isolated from the venom of the marine cone snail
Cone snail
Conidae is a taxonomic family of minute to quite large sea snails, marine gastropod molluscs in the superfamily Conoidea.The snails within this family are sophisticated predatory animals...
, genus Conus
Conus
Conus is a large genus of small to large predatory sea snails, marine gastropod molluscs, with the common names of cone snails, cone shells or cones. This genus is placed in the subfamily Coninae within the family Conidae. Geologically speaking, the genus is known from the Eocene to the Recent ...
.
Conotoxins, which are peptides consisting of 10 to 30 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
residues, typically have one or more disulfide bond
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...
s. Conotoxins have a variety of mechanisms of actions, most of which have not been determined. However it appears that many of these peptides modulate the activity of ion channel
Ion channel
Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
s.
Over the last few decades conotoxins have been subject of pharmacological interest.
Types and biological activities of conotoxins
The number of conotoxins whose activities have been determined so far is five, and they are called the α(alpha)-, δ(delta)-, κ(kappa)-, μ(mu)-, and ω(omega)- types. Each of the five types of conotoxins attacks a different target:- α-conotoxin inhibits nicotinic acetylcholine receptorAcetylcholine receptorAn acetylcholine receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.-Classification:...
s at nerveNerveA peripheral nerve, or simply nerve, is an enclosed, cable-like bundle of peripheral axons . A nerve provides a common pathway for the electrochemical nerve impulses that are transmitted along each of the axons. Nerves are found only in the peripheral nervous system...
s and muscleMuscleMuscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
s. - δ-conotoxin inhibits the inactivation of voltage-dependent sodium channels.
- κ-conotoxin inhibits potassium channelPotassium channelIn the field of cell biology, potassium channels are the most widely distributed type of ion channel and are found in virtually all living organisms. They form potassium-selective pores that span cell membranes...
s. - μ-conotoxin inhibits voltage-dependent sodium channels in muscles.
- ω-conotoxin inhibits N-type voltage-dependent calcium channelVoltage-dependent calcium channelVoltage-dependent calcium channels are a group of voltage-gated ion channels found in excitable cells with a permeability to the ion Ca2+...
s. Because N-type voltage-dependent calcium channels are related to algesiaAlgesiaAlgesia, from the Greek word algesis, is the sensitivity to pain. The term is sometimes used to refer to hyperalgesia .Analgesics, most commonly known as painkillers, are used to reduce the feeling of pain....
(sensitivity to painPainPain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
) in the nervous system, ω-conotoxin has an analgesicAnalgesicAn analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
effect: the effect of ω-conotoxin M VII A is 100 to 1000 times that of morphineMorphineMorphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
. Therefore a synthetic version of ω-conotoxin M VII A has found application as an analgesic drug ziconotide (Prialt).
Disulfide connectivities
Types of conotoxins also differ in the number and pattern of disulfide bonds. The disulfide bonding network, as well as specific amino acids in inter-cysteine loops, provide the specificity of conotoxins.Omega, delta and kappa conotoxins
Omega, delta and kappa families of conotoxins have a knottin or inhibitor cysteine knot scaffold. The knottin scaffold is a very special disulfide-through-disulfide knot, in which the III-VI disulfide bond crosses the macrocycle formed by two other disulfide bonds (I-IV and II-V) and the interconnecting backbone segments, where I-VI indicates the six cysteine residues starting from the N-terminus. The cysteine arrangements are the same for omega, delta and kappa families, even though omega conotoxins are calcium channel blockers, whereas delta conotoxins delay the inactivation of sodium channels, and kappa conotoxins are potassium channel blockers.Mu conotoxins
Mu-conotoxins have two types of cysteine arrangements, but the knottin scaffold is not observed. Mu-conotoxins target the muscle-specific voltage-gated sodium channels, and are useful probes for investigating voltage-dependent sodium channels of excitable tissues. Mu-conotoxins target the voltage-gated sodiumSodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
channels, preferentially those of skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
, and are useful probes for investigating voltage-dependent sodium channels of excitable tissue
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
s.
Different subtypes of voltage-gated sodium channels are found in different tissues in mammals, eg., in muscle and brain, and studies have been carried out to determine the sensitivity and specificity of the mu-conotoxins for the different isoforms.