Apamin
Encyclopedia
Apamin is an 18 amino acid peptide
neurotoxin
found in apitoxin
(bee
venom
). It selectively blocks SK channel
s, a type of Ca2+-activated K+ channel expressed in the central nervous system
and smooth muscle
. Due to its specificity for SK channels, apamin is used as a drug in biomedical research to study the electrical properties of SK channel
s and their role in the after hyperpolarization
s occurring immediately following an action potential
.
of the honeybee consists of many more products, like melittin
, the MCD peptide
and phospholipase A2
.
sequence of H-Cys-Asn-Cys-Lys-Ala-Pro-Glu-Thr-Ala-Leu-Cys-Ala-Arg-Arg-Cys-Gln-Gln-His-NH2 (with disulfide bonds between Cys1-Cys11 and Cys3-Cys15). Because honeybee venom is a complex mixture of short peptides and protein
s, it is difficult to isolate apamin. The isolation can be done by electrophoresis
, or by chromatography
.
and spinal cord
and inhibits them. It inhibits the three cloned SK channel subtypes (SK1, SK2, and SK3) with different affinity, highest affinity for SK2, lowest for SK1, and intermediate for SK3 channels. Heteromers show intermediate sensitivity. Most likely, apamin acts as a pore blocker, although residues both inside and outside of the pore region of the SK channels participate in apamin binding. The SK channels are present in a wide range of excitable and non-excitable cells, including cells in the central nervous system, intestinal myocytes, endothelial cells, and hepatocytes.
SK channels, when activated, contribute to afterhyperpolarizations in neuron
s, which control neuronal excitability. Intracellular Ca2+ binding to calmodulin
can activate these channels. Channel deactivation can take place through dissociation of Ca2+ from calmodulin. Inhibition of SK channels by apamin will increase the neuronal excitability and lower the threshold for generating an action potential
. Other toxins that block SK channels are tamapin
and scyllatoxin
.
Patients poisoned with bee venom can be treated with anti-inflammatory
medication, antihistamine
s and oral prednisolone
.
blockers such as apamin can have therapeutic applications, for example on the peripheral cells (e.g. the insulin
releasing cells of the pancreas
) and on the central nervous system
where there is evidence for a role of SK channels in memory
processes, both general and specifically hippocampal
.
SK channels have been proposed as targets for the treatment of ataxia
, epilepsy
, memory disorder
s, and possibly schizophrenia
and Parkinson's disease
.
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...
neurotoxin
Neurotoxin
A neurotoxin is a toxin that acts specifically on nerve cells , usually by interacting with membrane proteins such as ion channels. Some sources are more general, and define the effect of neurotoxins as occurring at nerve tissue...
found in apitoxin
Apitoxin
Apitoxin, or honey bee venom, is a bitter colorless liquid. The active portion of the venom is a complex mixture of proteins, which causes local inflammation and acts as an anticoagulant. The venom is produced in the abdomen of worker bees from a mixture of acidic and basic secretions. Apitoxin...
(bee
Bee
Bees are flying insects closely related to wasps and ants, and are known for their role in pollination and for producing honey and beeswax. Bees are a monophyletic lineage within the superfamily Apoidea, presently classified by the unranked taxon name Anthophila...
venom
Venom
Venom is the general term referring to any variety of toxins used by certain types of animals that inject it into their victims by the means of a bite or a sting...
). It selectively blocks SK channel
SK channel
SK channels are a subfamily of Ca2+-activated K+ channels. They are so called because of their small single channel conductance, ~10 pS. SK channels are a type of ion channel allowing potassium cations to cross the cell membrane and are activated by an increase in the concentration of...
s, a type of Ca2+-activated K+ channel expressed in the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
and smooth muscle
Smooth muscle
Smooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...
. Due to its specificity for SK channels, apamin is used as a drug in biomedical research to study the electrical properties of SK channel
SK channel
SK channels are a subfamily of Ca2+-activated K+ channels. They are so called because of their small single channel conductance, ~10 pS. SK channels are a type of ion channel allowing potassium cations to cross the cell membrane and are activated by an increase in the concentration of...
s and their role in the after hyperpolarization
Hyperpolarization (biology)
Hyperpolarization is a change in a cell's membrane potential that makes it more negative. It is the opposite of a depolarization.Hyperpolarization is often caused by efflux of K+ through K+ channels, or influx of Cl– through Cl– channels. On the other hand, influx of cations, e.g...
s occurring immediately following an action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
.
Origin
Apamin is a neurotoxin that was originally isolated from Apis mellifera, the Western honey bee. The venomVenom
Venom is the general term referring to any variety of toxins used by certain types of animals that inject it into their victims by the means of a bite or a sting...
of the honeybee consists of many more products, like melittin
Melittin
Melittin is the principal active component of apitoxin and is a powerful stimulator of phospholipase A2. Melittin is a peptide consisting of 26 amino acids with the sequence GIGAVLKVLTTGLPALISWIKRKRQQ.-Biological effects:...
, the MCD peptide
MCD peptide
Mast cell degranulating peptide is a cationic 22-amino acid residue peptide, which is a component of the venom of the bumblebee . At low concentrations, MCD peptide can stimulate mast cell degranulation. At higher concentrations, it has anti-inflammatory propterties...
and phospholipase A2
Phospholipase A2
Phospholipases A2 are enzymes that release fatty acids from the second carbon group of glycerol. This particular phospholipase specifically recognizes the sn-2 acyl bond of phospholipids and catalytically hydrolyzes the bond releasing arachidonic acid and lysophospholipids...
.
Chemistry
Apamin is a polypeptide possessing an amino acidAmino 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...
sequence of H-Cys-Asn-Cys-Lys-Ala-Pro-Glu-Thr-Ala-Leu-Cys-Ala-Arg-Arg-Cys-Gln-Gln-His-NH2 (with disulfide bonds between Cys1-Cys11 and Cys3-Cys15). Because honeybee venom is a complex mixture of short peptides and protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s, it is difficult to isolate apamin. The isolation can be done by electrophoresis
Electrophoresis
Electrophoresis, also called cataphoresis, is the motion of dispersed particles relative to a fluid under the influence of a spatially uniform electric field. This electrokinetic phenomenon was observed for the first time in 1807 by Reuss , who noticed that the application of a constant electric...
, or by chromatography
Chromatography
Chromatography is the collective term for a set of laboratory techniques for the separation of mixtures....
.
Pharmacology
Apamin binds to the SK channels (small conductance Ca2+-activated K+ channels) in the brainBrain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
and spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
and inhibits them. It inhibits the three cloned SK channel subtypes (SK1, SK2, and SK3) with different affinity, highest affinity for SK2, lowest for SK1, and intermediate for SK3 channels. Heteromers show intermediate sensitivity. Most likely, apamin acts as a pore blocker, although residues both inside and outside of the pore region of the SK channels participate in apamin binding. The SK channels are present in a wide range of excitable and non-excitable cells, including cells in the central nervous system, intestinal myocytes, endothelial cells, and hepatocytes.
SK channels, when activated, contribute to afterhyperpolarizations in neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s, which control neuronal excitability. Intracellular Ca2+ binding to calmodulin
Calmodulin
Calmodulin is a calcium-binding protein expressed in all eukaryotic cells...
can activate these channels. Channel deactivation can take place through dissociation of Ca2+ from calmodulin. Inhibition of SK channels by apamin will increase the neuronal excitability and lower the threshold for generating an action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
. Other toxins that block SK channels are tamapin
Tamapin
Tamapin is a toxin from the Indian Red Scorpion , which is a selective and potent blocker of SK2 channels.- Chemical structure & methods of isolation :...
and scyllatoxin
Scyllatoxin
Scyllatoxin is a toxin, from the scorpion Leiurus quinquestriatus hebraeus, which blocks small-conductance Ca2+-activated K+ channels.- Source :...
.
Toxicity
Symptoms following bee sting or apamin poisoning may include:- local effects: burning or stinging 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."...
, swellingSwelling (medical)In medical parlance, swelling is the transient enlargement or protuberance in the body and may include tumors. According to cause, it may be congenital, traumatic, inflammatory, neoplastic or miscellaneous....
, redness. - severe systemic reactions: swelling of the tongueTongueThe tongue is a muscular hydrostat on the floors of the mouths of most vertebrates which manipulates food for mastication. It is the primary organ of taste , as much of the upper surface of the tongue is covered in papillae and taste buds. It is sensitive and kept moist by saliva, and is richly...
and throatThroatIn vertebrate anatomy, the throat is the anterior part of the neck, in front of the vertebral column. It consists of the pharynx and larynx...
, difficulty breathingBreathingBreathing is the process that moves air in and out of the lungs. Aerobic organisms require oxygen to release energy via respiration, in the form of the metabolism of energy-rich molecules such as glucose. Breathing is only one process that delivers oxygen to where it is needed in the body and...
, and shock. - development of optic neuritisOptic neuritisOptic neuritis is the inflammation of the optic nerve that may cause a complete or partial loss of vision.-Causes:The optic nerve comprises axons that emerge from the retina of the eye and carry visual information to the primary visual nuclei, most of which is relayed to the occipital cortex of the...
and atrophyAtrophyAtrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations , poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply to the target organ, disuse or lack of exercise or disease intrinsic to the tissue itself...
. - atrial fibrillationAtrial fibrillationAtrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...
, cerebral infarctionCerebral infarctionA cerebral infarction is the ischemic kind of stroke due to a disturbance in the blood vessels supplying blood to the brain. It can be atherothrombotic or embolic. Stroke caused by cerebral infarction should be distinguished from two other kinds of stroke: cerebral hemorrhage and subarachnoid...
, acute myocardial infarctionMyocardial infarctionMyocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
, Fisher's syndrome, acute inflammatory polyradiculopathy (Guillain-Barre syndromeGuillain-Barré syndromeGuillain–Barré syndrome , sometimes called Landry's paralysis, is an acute inflammatory demyelinating polyneuropathy , a disorder affecting the peripheral nervous system. Ascending paralysis, weakness beginning in the feet and hands and migrating towards the trunk, is the most typical symptom...
), claw handClaw handClaw hand can refer to:* Ectrodactyly* A symptom of Ulnar nerve entrapment. See Ulnar claw...
(through a central action of apamin on the spinal cordSpinal cordThe spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
and a peripheral action in the form of median and ulnaUlnaThe ulna is one of the two long bones in the forearm, the other being the radius. It is prismatic in form and runs parallel to the radius, which is shorter and smaller. In anatomical position The ulna is one of the two long bones in the forearm, the other being the radius. It is prismatic in form...
r neuritis, causing spasms of the long flexors in the forearmForearm-See also:*Forearm flexors*Forearm muscles...
). - dramatic haemorrhagic effectBleedingBleeding, technically known as hemorrhaging or haemorrhaging is the loss of blood or blood escape from the circulatory system...
in the lungLungThe lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
s.
Patients poisoned with bee venom can be treated with anti-inflammatory
Anti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....
medication, antihistamine
Antihistamine
An H1 antagonist is a histamine antagonist of the H1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions...
s and oral prednisolone
Prednisolone
Prednisolone is the active metabolite of prednisone, which is also used as a drug.-Uses:Prednisolone is a corticosteroid drug with predominant glucocorticoid and low mineralocorticoid activity, making it useful for the treatment of a wide range of inflammatory and auto-immune conditions such as...
.
Therapeutic Use
SK channelSK channel
SK channels are a subfamily of Ca2+-activated K+ channels. They are so called because of their small single channel conductance, ~10 pS. SK channels are a type of ion channel allowing potassium cations to cross the cell membrane and are activated by an increase in the concentration of...
blockers such as apamin can have therapeutic applications, for example on the peripheral cells (e.g. the insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
releasing cells of the pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
) and on the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
where there is evidence for a role of SK channels in memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
processes, both general and specifically hippocampal
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
.
SK channels have been proposed as targets for the treatment of ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
, epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
, memory disorder
Memory disorder
Memory can be defined as an organism's ability to encode, retain, and recall information. Disorders of memory can range from mild to severe, yet are all a result of damage to neuroanatomical structures; either in part or in full. This damage hinders the storage, retention and recollection of memories...
s, and possibly schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
and Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
.