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1  structure 1  species 0  interactions 5  sequences 1  architecture

Family: Bee_toxin (PF17454)

Summary: Honey bee toxin

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This is the Wikipedia entry entitled "Apamin". More...

Apamin Edit Wikipedia article

Apamin[1]
Apamin.svg
Identifiers
3D model (Jmol)
ChemSpider
ECHA InfoCard 100.041.969
Properties
C79H131N31O24S4
Molar mass 2027.33874 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YesYN ?)
Infobox references
Apamin Preproprotein
Identifiers
Symbol Apamin
CAS number 24345-16-2
Entrez 406135
UniProt P01500

Apamin is an 18 amino acid peptide neurotoxin found in apitoxin (bee venom).[2] Dry bee venom consists of 2-3% of apamin.[3] Apamin selectively blocks SK channels, a type of Ca2+-activated K+ channel expressed in the central nervous system. Toxicity is caused by only a few amino acids, these are cysteine1, lysine4, arginine13, arginine14 and histidine18. These amino acids are involved in the binding of apamin to the Ca2+-activated K+ channel. Due to its specificity for SK channels, apamin is used as a drug in biomedical research to study the electrical properties of SK channels and their role in the afterhyperpolarizations occurring immediately following an action potential.[4]

Origin

The first symptoms of apitoxin (bee venom), that are now thought to be caused by apamin, were described back in 1936 by Hahn and Leditschke. Apamin was first isolated by Habermann in 1965 from Apis mellifera, the Western honey bee. Apamin was named after this bee. Bee venom contains many other compounds, like histamine, phospholipase A2, hyaluronidase, MCD peptide, and the main active component melittin. Apamin was separated from the other compounds by gel filtration and ion exchange chromatography.[2]

Structure and active site

Apamin is a polypeptide possessing an amino acid 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). Apamin is very rigid because of the two disulfide bridges and seven hydrogen bonds. The three-dimensional structure of apamin has been studied with several spectroscopical techniques: HNMR, Circular Dichroism, Raman spectroscopy, FT-IR. The structure is presumed to consist of an alpha-helix and beta-turns, but the exact structure is still unknown.[5]

By local alterations it is possible to find the amino acids that are involved in toxicity of apamin. It was found by Vincent et al. that guanidination of the ε-amino group of lysine4 does not decrease toxicity. When the ε-amino group of lysine4 and the α-amino group of cysteine1 are acetylated or treated with fluorescamine, toxicity decreases with a factor of respectively 2.5 and 2.8. This is only a small decrease, which indicates that neither the ε-amino group of lysine4 nor the α-amino group of cysteine1 is essential for the toxicity of apamin. Glutamine7 was altered by formation of an amide bond with glycine ethyl ester, this resulted in a decrease in toxicity of a factor 2.0. Glutamine7 also doesn't appear to be essential for toxicity. When histidine18 is altered by carbethoxylation, toxicity decreases only by a factor 2.6. But when histidine18, the ε-amino group of lysine4 and the α-amino group of cysteine1 all are carbethoxylated and acetylated toxicity decreases drastically. This means that these three amino acids are not essential for toxicity on their own, but the three of them combined are. Chemical alteration of arginine13 and arginine14 by treatment of 1,2-cyclohexanedione and cleavage by trypsin decreases toxicity by a factor greater than 10. The amino acids that cause toxicity of apamin are cysteine1, lysine4, arginine13, arginine14 and histidine18.[6]

Toxicodynamics

Apamin is the smallest neurotoxin polypeptide known, and the only one that passes the blood-brain barrier.[6] Apamin thus reaches its target organ, the central nervous system. Here it inhibits small-conductance Ca2+-activated K+ channels (SK channels) in neurons. These channels are responsible for the afterhyperpolarizations that follow action potentials, and therefore regulate the repetitive firing frequency.[7] Three different types of SK channels show different characteristics. Only SK2 and SK3 are blocked by apamin, whereas SK1 is apamin insensitive. SK channels function as a tetramer of subunits. Heteromers have intermediate sensitivity.[7] SK channels are activated by the binding of intracellular Ca2+ to the protein calmodulin, which is constitutively associated to the channel.[8] Transport of potassium ions out of the cell along their concentration gradient causes the membrane potential to become more negative. 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.

Binding of apamin to SK channels is mediated by amino acids in the pore region as well as extracellular amino acids of the SK channel.[9] It is likely that the inhibition of SK channels is caused by blocking of the pore region, which hinders the transport of potassium ions. This will increase the neuronal excitability and lower the threshold for generating an action potential. Other toxins that block SK channels are tamapin and scyllatoxin.

Toxicokinetics

The kinetics of labeled derivatives of apamin were studied in vitro and in vivo in mice by Cheng-Raude et al. This shed some light on the kinetics of apamin itself. The key organ for excretion is likely to be the kidney, since enrichment of the labeled derivatives was found there. The peptide apamin is small enough to pass the glomerular barrier, facilitating renal excretion. The central nervous system, contrarily, was found to contain only very small amounts of apamin. This is unexpected, as this is the target organ for neurotoxicity caused by apamin. This low concentration thus appeared to be sufficient to cause the toxic effects.[10]

However, these results disagree with a study of Vincent et al. After injection of a supralethal dose of radioactive acetylated apamin in mice, enrichment was found in the spinal cord, which is part of the target organ. Some other organs, including kidney and brain, contained only small amounts of the apamin derivative.[6]

Symptoms

Symptoms following bee sting may include:

Patients poisoned with bee venom can be treated with anti-inflammatory medication, antihistamines and oral prednisolone.[11]

Apamin is an element in bee venom. You can come into contact with apamin through bee venom, so the symptoms that are known are not caused by apamin directly, but by the venom as a whole. Apamin is the only neurotoxin acting purely on the central nervous system. The symptoms of apamin toxicity are not well known, because people are not easily exposed to the toxin alone.[12]

Through research about the neurotoxicity of apamin some symptoms were discovered. In mice, the injection of apamin produces convulsions and long-lasting spinal spasticity. Also it is known that the polysynaptic spinal reflexes are disinhibited in cats.[12] Polysynaptic reflex is a reflex action that transfers an impulse from a sensory neuron to a motor neuron via an interneuron in the spinal cord.[13] In rats, apamin was found to cause tremor and ataxia, as well as dramatic haemorrhagic effects in the lungs.[14]

Furthermore, apamin has been found to be 1000 times more efficient when applied into the ventricular system instead of the peripheral nervous system. The ventricular system is a set of structures in the brain containing cerebrospinal fluid. The peripheral nervous system contains the nerves and ganglia outside of the brain and spinal cord.[12] This difference in efficiency can easily be explained. Apamin binds to the SK channels, which differ slightly in different tissues. So apamin binding is probably stronger in SK channels in the ventricular system than in other tissues.

Toxicity rates

In earlier years it was thought that apamin was a rather nontoxic compound (LD50 = 15 mg/kg in mice) compared to the other compounds in bee venom.[15] The current lethal dose values of apamin measured in mice are given below.[16] There are no data known specific for humans.

Intraperitoneal (mouse) LD50: 3.8 mg/kg

Subcutaneous (mouse) LD50: 2.9 mg/kg

Intravenous (mouse) LD50: 4 mg/kg

Intracerebral (mouse) LD50: 1800 ng/kg

Parenteral (mouse) LD50: 600 mg/kg

Therapeutic use

Recent studies have shown that SK channels do not only regulate afterhyperpolarization, they also have an effect on synaptic plasticity. This is the activity-dependent adaptation of the strength of synaptic transmission. Synaptic plasticity is an important mechanism underlying learning and memory processes. Apamin is expected to influence these processes by inhibiting SK channels. It has been shown that apamin enhances learning and memory in rats and mice.[7][17] This may provide a basis for the use of apamin as a treatment for memory disorders and cognitive dysfunction. However, due to the risk of toxic effects, the therapeutic window is very narrow.[17]

SK channel blockers may have a therapeutic effect on Parkinson's disease. Dopamine, which is depleted in this disease, will be released from midbrain dopaminergic neurons when these SK channels are inhibited. SK channels have also been proposed as targets for the treatment of epilepsy, emotional disorders and schizophrenia.[17]

References

  1. ^ Apamin - Compound Summary, PubChem.
  2. ^ a b Habermann E (1984). "Apamin". Pharmacology & Therapeutics. 25 (2): 255–70. doi:10.1016/0163-7258(84)90046-9. PMID 6095335. 
  3. ^ Son DJ, Lee JW, Lee YH, Song HS, Lee CK, Hong JT (Aug 2007). "Therapeutic application of anti-arthritis, pain-releasing, and anti-cancer effects of bee venom and its constituent compounds". Pharmacology & Therapeutics. 115 (2): 246–70. doi:10.1016/j.pharmthera.2007.04.004. PMID 17555825. 
  4. ^ Castle NA, Haylett DG, Jenkinson DH (Feb 1989). "Toxins in the characterization of potassium channels". Trends in Neurosciences. 12 (2): 59–65. doi:10.1016/0166-2236(89)90137-9. PMID 2469212. 
  5. ^ Kastin AJ. Apamin. handbook of biologically active peptides (2013 ed.). pp. 417–418. 
  6. ^ a b c Vincent JP, Schweitz H, Lazdunski M (Jun 1975). "Structure-function relationships and site of action of apamin, a neurotoxic polypeptide of bee venom with an action on the central nervous system". Biochemistry. 14 (11): 2521–5. doi:10.1021/bi00682a035. PMID 1138869. 
  7. ^ a b c M. Stocker; M. Krause; P. Pedarzani (1999). "An apamin-sentisitive Ca2+-activated K+ current in hippocampal pyramidal neurons". PNAS. 96 (8). doi:10.1073/pnas.96.8.4662. 
  8. ^ Stocker M (Oct 2004). "Ca(2+)-activated K+ channels: molecular determinants and function of the SK family". Nature Reviews. Neuroscience. 5 (10): 758–70. doi:10.1038/nrn1516. PMID 15378036. 
  9. ^ Nolting A, Ferraro T, D'hoedt D, Stocker M (Feb 2007). "An amino acid outside the pore region influences apamin sensitivity in small conductance Ca2+-activated K+ channels". The Journal of Biological Chemistry. 282 (6): 3478–86. doi:10.1074/jbc.M607213200. PMC 1849974Freely accessible. PMID 17142458. 
  10. ^ Cheng-Raude D, Treloar M, Habermann E (1976). "Preparation and pharmacokinetics of labeled derivatives of apamin". Toxicon. 14 (6): 467–76. doi:10.1016/0041-0101(76)90064-7. PMID 1014036. 
  11. ^ a b Saravanan R, King R, White J (Apr 2004). "Transient claw hand owing to a bee sting. A report of two cases". The Journal of Bone and Joint Surgery. British Volume. 86 (3): 404–5. doi:10.1302/0301-620x.86b3.14311. PMID 15125129. 
  12. ^ a b c Habermann E (Nov 1977). "Neurotoxicity of apamin and MCD peptide upon central application". Naunyn-Schmiedeberg's Archives of Pharmacology. 300 (2): 189–91. doi:10.1007/bf00505050. PMID 593441. 
  13. ^ "polysynaptic reflex". 
  14. ^ Lallement G, Fosbraey P, Baille-Le-Crom V, Tattersall JE, Blanchet G, Wetherell JR, Rice P, Passingham SL, Sentenac-Roumanou H (Dec 1995). "Compared toxicity of the potassium channel blockers, apamin and dendrotoxin". Toxicology. 104 (1-3): 47–52. doi:10.1016/0300-483X(95)03120-5. PMID 8560501. 
  15. ^ department of the army Edgewood Arsenal biodemical laboratory (1972). "Beta adrenergic and antiarrhythmic effect of apamin, a component of bee venom". 
  16. ^ "Apamin" (PDF). Material Safety Data Sheet. 
  17. ^ a b c Faber ES, Sah P (Oct 2007). "Functions of SK channels in central neurons". Clinical and Experimental Pharmacology & Physiology. 34 (10): 1077–83. doi:10.1111/j.1440-1681.2007.04725.x. PMID 17714097. 

External links

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This is the Wikipedia entry entitled "MCD peptide". More...

MCD peptide Edit Wikipedia article

The amino acid sequence of MCD peptide [1]
Met - Cys - Ile - Cys - Lys - Asn - Gly - Lys - Pro - Leu - Pro - Gly - Phe - Ile - Gly - Lys - Ile - Cys - Arg - Lys - Ile - Cys - Met - Met - Gln - Gln -Thr - His(NH2)

Mast cell degranulating (MCD) peptide is a cationic 22-amino acid residue peptide, which is a component of the venom of the bumblebee (Megabombus pennsylvanicus). At low concentrations, MCD peptide can stimulate mast cell degranulation. At higher concentrations, it has anti-inflammatory propterties. In addition, it is a potent blocker of voltage-sensitive potassium channels.

Sources

MCD peptide is a component of bumblebee (Megabombus pennsylvanicus) venom.[2] In addition to MCD peptide, melittin and apamin have also been identified in this venom and are also described as voltage-dependent channel blockers. MCD peptide is also present in the venom of the honey bee Apis mellifera.[3]

Chemistry

MCD peptide is a cationic 22-amino acid residue peptide with two disulfide bridges.[4] Although the MCD peptide sequence shows similarity with apamin,[5] they have different toxic properties. MCD peptide belongs to a large family composed of numerous derivatives detecting specific targets and displaying different toxic effects.[4]

Targets

MCD peptide has immunotoxic as well as neurotoxic properties due to different active sites of the MCD peptide.[6] The MCD peptide has an immunotoxic effect on mast cells [1] by releasing histamine from these cells.[7] MCD peptide has also been described as a potent modulator of voltage-gated ionic channels. It binds to several subclasses of voltage-gated potassium channels (Kv channels), including Kv1.1, Kv1.6, and less potently to Kv1.2.[8][9][10][11] Accordingly, MCD peptide can act in various regions of rat brain, including cerebellum, brainstem, hypothalamus, striatum, midbrain, cortex,[6][12] and hippocampus.[6] However, MCD peptide shows no binding activity in the peripheral neuronal system.[12]

Mode of action

For its immunotoxic properties, a low concentration of MCD peptide can cause mast cell degranulation by releasing histamine; at higher concentrations it displays anti-inflammatory activities.[6]

Through its effect on ionic channels, MCD peptide can induce long term potentiation (LTP) in CA1 region of hippocampus.[13] It binds and inactivates voltage-dependent K+ channels, including fast-inactivating (A-type) and slow-inactivating (delayed rectifier) K+ channels. The binding site of the MCD peptide on the K+ ion channel protein complex is a multimeric protein, consisting of polypeptide chains of molecular weight between 76,000-80,000 and 38,000 Daltons.[14] By blocking potassium channels, the MCD peptide can increase the duration of action potentials and increase neuronal excitability.[6]

Toxicity

The neurotoxicity of MCD peptide is distincted from its histamine releasing function.[2] The histamine releasing function of MCD peptide, at low concentrations, causes the degranulation of mast cell [4] ,[13] and shows anti-inflammatory activity at higher concentrations.[4][15] These actions of MCD peptide on mast cells is thought to be involved in allergic and inflammatory processes related to type I hypersensitivity reaction.[16]

MCD peptide shows neurotoxicity by inducing epileptiform seizures in rat, when intraventricularly injected. This toxicity is caused by the blockage of voltage-gated potassium channels by the MCD peptide.[15] However, there is no toxicity of MCD administered peripherally, even at high doses.[12]

Therapeutic use

As a mast cell activator, the MCD peptide evokes large increases in antigen-specific serum immunoglobulin G (IgG) responses.[17] Therefore, it is used as a vaccine adjuvant. MCD peptide analogs, such as [Ala12] MCD, provide a base for designing agents that can prevent IgE/Fc-RIa interactions and reduce allergic conditions.[18][19]

References

  1. ^ a b Argiolas, A; Herring, P; Pisano, JJ (1985). "Amino Acid Sequence of Bumblebee MCD Peptide: A New Mast Cell Degranulating Peptide From the Venom of the Bumblebee Megabombus pennsylvanicus". Peptides. 6 (3): 431–436. doi:10.1016/0196-9781(85)90410-3. PMID 2421265. 
  2. ^ a b Breithaupt, H; Habermann, E (1968). "Mastzelldegranulierendes Peptid (MCD-Peptid) aus Bienengift: Isolierung, biochemische und pharmakologische Eigenschaften". Naunyn-Schmiedebergs Arch. Pharmak. Exp. Path. 261 (3): 252–270. doi:10.1007/BF00536989. 
  3. ^ Bessone, R; Martin-Eauclaire, MF; Crest, M; Mourre, C (2004). "Heterogeneous competition of Kv1 channel toxins with kaliotoxin for binding in rat brain: autoradiographic analysis". Neurochem Int. 45 (7): 1039–47. doi:10.1016/j.neuint.2004.05.006. PMID 15337303. 
  4. ^ a b c d Buku, A (1999). "Mast cell degranulating (MCD) peptide: a prototypic peptide in allergy and inflammation". Peptides. 20 (3): 415–20. doi:10.1016/S0196-9781(98)00167-3. PMID 10447103. 
  5. ^ Gmachl, M; Kreil, G (1995). "The precursors of the bee Venom Constituents Apamin and MCD Peptide Are Encoded by two Genes in Tandem Which Share the Same 3'- Exon". J Biol Chem. 270 (21): 12704–12708. doi:10.1074/jbc.270.21.12704. PMID 7759523. 
  6. ^ a b c d e Dreyer, F (1990). "Peptide Toxins and potassium channels". Rev. Physiol. Biochem. Pharmacol. 115. 
  7. ^ King, TP; Jim, SY; Wittkowski, KM (2003). "Inflammatory role of two venom components of yellow jackets (Vespula vulgaris): a mast cell degranulating peptide mastoparan and phospholipase A1". Int. Arch. Allergy Immunol. 131 (1): 25–32. doi:10.1159/000070431. PMID 12759486. 
  8. ^ Pongs, O (1992). "Molecular biology of voltage-dependent potassium channels". Physiol. Rev. 72: 69–88. 
  9. ^ Grissmer, S; Nguyen, AN; Aiyar, J; Hanson, DC; Mather, RJ; Gurman, GA; Karmilowicz, MJ; Auperin, DD; Chandy, KG (1994). "Pharmacological characterization of five cloned voltage-gated K+ channels, types Kv1.1, 1.2, 1.3, 1.5, and 3.1, stably expressed in mammalian cell lines". Mol Pharmacol. 45 (6): 1227–1234. PMID 7517498. 
  10. ^ Harvey, AL (1997). "Recent studies on dendrotoxins and potassium ion channels". Gen. Pharmacol. 28 (1): 7–12. doi:10.1016/S0306-3623(96)00173-5. PMID 9112070. 
  11. ^ Stühmer, M; Ruppersberg, J; Schröter, K; Sakmann, B; Stocker, M; Giese, K; Perschke, A; Baumann, A; Pongs, O (1989). "Molecular basis of functional diversity of voltage-gated potassium channels in mammalian brain". EMBO J. 8 (11): 3235–3244. PMC 401447Freely accessible. PMID 2555158. 
  12. ^ a b c Taylor, J; Bidard, J; Lazdunski, M (1984). "The characterization of high affinity binding sites in rat brain for the mast cell degranulating peptide from bee venom using purified monoiodinated peptide". J Biol Chem. 259 (2): 13957–13967. PMID 6501283. 
  13. ^ a b Cherubini, E; Ben Ari, Y; Gho, M; Bidard, JN; Lazdunski, M (1987). "Long-term potentiation of synaptic transmission in the hippocampus induced by a bee venom peptide". Nature. 328 (6125): 70–3. doi:10.1038/328070a0. PMID 2885754. 
  14. ^ Rehm, H; Lazdunski, M (1988). "Purification and subunit structure of a putative K+-channel protein identified by its binding properties for dendrotoxin I". Proc. Natl. Acad. Sci. USA. 85 (13): 4919–23. doi:10.1073/pnas.85.13.4919. PMC 280549Freely accessible. PMID 2455300. 
  15. ^ a b Ziai, M; Russek, S; Wang, H; Beer, B; Blume, A (1990). "Mast cell degranulating peptide: a multi-functional neurotoxin". J Pharm Pharmacol. 42 (7): 457–461. doi:10.1111/j.2042-7158.1990.tb06595.x. PMID 1703229. 
  16. ^ Schwartz, L (1994). "Mast cells function and contents". Curr. Opin. Immunol. 6 (1): 91–97. doi:10.1016/0952-7915(94)90039-6. PMID 8172685. 
  17. ^ McLachlan, J; Shelburne, C; Hart, J; Pizzo, S; Goyal, R; Brooking-Dixon, R; Staats, H; Abraham, S (2008). "Mast cell activators: a new class of highly effective vaccine adjuvants". Nat Med. 14 (5): 536–41. doi:10.1038/nm1757. PMID 18425129. 
  18. ^ Buku, A; Condie, BA; Price, JA; Mezei, M (2005). "[Ala12]MCD peptide: a lead peptide to inhibitors of immunoglobulin E binding to mast cell receptors". J Pept Res. 66 (3): 132–137. doi:10.1111/j.1399-3011.2005.00281.x. PMID 16083440. 
  19. ^ Buku, A; Priceb, JA; Mendlowitzc, M; Masurd, S (2001). "Mast cell degranulating peptide binds to RBL-2H3 mast cell receptors and inhibits IgE binding". Peptides. 22 (12): 1993–1998. doi:10.1016/S0196-9781(01)00542-3. PMID 11786182. 

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This is the Wikipedia entry entitled "Tertiapin". More...

Tertiapin Edit Wikipedia article

Tertiapin is a 21-amino acid peptide isolated from venom of the European honey bee (Apis mellifera). It blocks two different types of potassium channels, inward rectifier potassium channels (Kir) and calcium activated large conductance potassium channels (BK).

Tertiapin peptide

Sources

Tertiapin is a peptidic component of the venom of the European honey bee (Apis mellifera).[1]

Chemistry

Tertiapin peptide is composed of 21 amino acids with the sequence: Ala-Leu-Cys-Asn-Cys-Asn-Arg-Ile-Ile-Ile-Pro-His-Met-Cys-Trp-Lys-Lys-Cys-Gly-Lys-Lys.[2]
The methionine residue is sensitive to oxidation, reducing the ability to block the ionic channels. Methionine can be substituted by glutamine in order to prevent the oxidation. The new synthesized peptide is named Tertiapin-Q and does not show any functional change as compared to the original peptide, which makes it a more suitable research tool.[3]

Target and mode of action

Tertiapin has been described as a potent potassium channel blocker, acting on two different types of K+ channels.

Inward rectifier potassium channels

Tertiapin binds specifically to different subunits of the inward rectifier potassium channel (Kir), namely GIRK1 (Kir 3.1), GIRK4 (Kir 3.4) and ROMK1 (Kir 1.1), inducing a dose-dependent block of the potassium current.[2] It is thought that tertiapin binds to the Kir channel with its α-helix situated at the C-terminal of the peptide. This α-helix is plugged into the external end of the conduction pore, thereby blocking the channel. The N-terminal of the peptide sticks out of the extracellular side.[4] Tertiapin has a high affinity for Kir channels with approximately Kd = 8 nM for GIRK1/4 channels and Kd = 2 nM for ROMK1 channels.[2]
[5] In contrast to the voltage-gated K+ channels, Kir channels are more permeable to K+ during hyperpolarization than during depolarization. A voltage-dependent blockade by intracellular cations at voltages more positive than the K+ reversal potential is the mechanism underlying this feature. At more negative voltages the Kir channels are responsible for an inward K+ current. Therefore Kir channels contribute to the maintenance of the resting potential, the duration of the action potential and the neuronal excitability.[6]
GIRK1 and -4 are subunits of the muscarinic potassium channels (KACh) and have an important role in the slowing down of the heart rate in response to parasympathetic stimulation via acetylcholine. KAch channels activate during hyperpolarization, prolonging the cardiac action potential by inflow of potassium ions and reducing the frequency of action potential generation. An inhibition by tertiapin will result in a shorter cardiac action potential with loss of parasympathetic control, resulting in a faster heart rate [7][8]
ROMK is found in the kidneys where it contributes to K+ recycling. An inhibition will result in loss of potassium, as observed in Bartter syndrome, which can be caused by mutations in the ROMK channels.[6]

BK channels

The second type of potassium channel that tertiapin blocks is the calcium activated large conductance potassium channel (BK). The block of BK cells is voltage-, concentration- and use-dependent, meaning the blockage changes with different stimulation voltages and frequencies, different concentrations and with the duration of application of tertiapin. The IC50 for BK channels is 5.8 nM.
The BK channels have a role in the onset of the afterhyperpolarization, thereby shortening the action potential and enhancing the speed of repolarization. Total blockage by tertiapin prolongs the duration of the action potential and inhibits the afterhyperpolarization amplitude, leading to an increase of the neuronal excitability.
Tertiapin inhibits the BK channels only after a minimal stimulation of 15 minutes, in contrast with less than a minute for the GIRK channels. For this reason it is thought that the mode of action of tertiapin is different for each channel type.[9]

Toxicity

Tertiapin is a compound of the honey bee venom (apitoxin) that causes pain and signs of inflammation around the sting, but a great number of stings can be lethal (LD50 is 18-22 stings per kg for humans).[10] An anaphylactic shock can develop if a person has an allergy to the venom. In that case even one sting can be lethal.

Therapeutic use

As a paradox to the symptoms after a bee sting, bee venom is used for treatment of pain, inflammation (e.g. rheumatoid arthritis) and multiple sclerosis. Tertiapin may contribute to this effect by prolonging the depolarization phase by blocking the BK channels. Eventually this will lead to inactivation of the voltage-gated Na+ channels of the dorsal root ganglion neurons, reducing sensory transmission to the central nervous system.[9]
Excessive stimulation with acetylcholine can induce an AV-block in the heart as shown in guinea pigs, which can be prevented by blockage of the KAch channels by tertiapin. This suggests a possible therapeutic role in excessive parasympathetic innervation or inferior myocardial infarction.[7]

References

  1. ^ Gauldie, J; Hanson, JM; Rumjanek, FD; Shipolini, RA; Vernon, CA (1976). "The peptide components of bee venom". European Journal of Biochemistry. 61 (2): 369–376. PMID 1248464. doi:10.1111/j.1432-1033.1976.tb10030.x. 
  2. ^ a b c Jin, W; Lu, Z (1998). "A novel high affinity inhibitor for inward-rectifier K+ channels". Biochemistry. 37 (38): 13291–13299. PMID 9748337. doi:10.1021/bi981178p. 
  3. ^ Jin, W; Lu, Z (1999a). "Synthesis of a stable form of tertiapin: a high-affinity inhibitor for inward-rectifier K+ channels". Biochemistry. 38 (43): 14286–14293. PMID 10572003. doi:10.1021/bi991205r. 
  4. ^ Jin, W; Klem, AM; Lewis, JH; Lu, Z (1999b). "Mechanisms of inward-rectifier K+ channel inhibition by tertiapin-Q". Biochemistry. 38 (43): 14294–14301. PMID 10572004. doi:10.1021/bi991206j. 
  5. ^ Foster, D. B.; Ho, A. S.; Rucker, J; Garlid, A. O.; Chen, L; Sidor, A; Garlid, K. D.; O'Rourke, B (2012). "Mitochondrial ROMK channel is a molecular component of mitoK(ATP)". Circulation Research. 111 (4): 446–54. PMC 3560389Freely accessible. PMID 22811560. doi:10.1161/CIRCRESAHA.112.266445. 
  6. ^ a b Isomoto, S; Kondo, C; Kurachi, Y (1997). "Inwardly rectifying potassium channels: their molecular heterogeneity and function". Japanese journal of physiology. 47 (1): 11–39. PMID 9159640. doi:10.2170/jjphysiol.47.11. 
  7. ^ a b Drici, MD; Diochot, S; Terrenoire, C; Romey, G; Lazdunski, M (2000). "The bee venom peptide tertiapin underlines the role of IKACh in acetylcholine-induced atrioventricular blocks". British Journal of Pharmacology. 131 (3): 569–577. PMC 1572365Freely accessible. PMID 11015309. doi:10.1038/sj.bjp.0703611. 
  8. ^ Kitamura, H; Yokoyama, M; Akita, H; Matsushita, K; Kurachi, Y; Yamada, M (1999). "Tertiapin potently and selectively blocks muscarinic K+ channels in rabbit cardiac myocytes". The Journal of Pharmacology and Experimental Therapeutics. 293 (1): 196–205. PMID 10734170. 
  9. ^ a b Kanjhan, R; Coulson, EJ; Adams, DJ; Bellingham, MC (2005). "Tertiapin-Q blocks recombinant and native large conductance K+ channels in a use-dependent manner". The Journal of Pharmacology and Experimental Therapeutics. 314 (3): 1353–1361. PMID 15947038. doi:10.1124/jpet.105.085928. 
  10. ^ Pankiw, T (2009). "Reducing honey bee defensive responses and social wasp colonization with methyl anthranilate". Journal of medical entomology. 46 (4): 782–788. PMID 19645280. doi:10.1603/033.046.0408. 

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Honey bee toxin Provide feedback

Bee venom contains a variety of peptides such as melittin, apamin, adolapin and mast cell degranulating peptide [1]. Bee venom has been used in the treatment of major neurodegenerative disorders, including Alzheimer’s Disease, Parkinson’s Disease, Epilepsy, Multiple Sclerosis and Amyotrophic Lateral Sclerosis [2]. Secondary structure analysis of apamin, mast cell degranulating peptide, tertiapin and secapin have been studied. The predicted structure for mast cell degranulating peptide is almost spherical with the eight positive centres evenly distributed over the surface. It has also been suggested that these four peptides share a common folding pattern, which is centred on a beta-turn covalently linked to an alpha-helical segment by two disulphide links. It is further suggested that apamin, mast cell degranulating peptide and tertiapin form a single molecular class [3]. This domain family is found in apamin, mast cell degranulating peptide and tertiapin. Apamin, the most widely studied member of this family has been shown to be a selective blocker of small-conductance Ca2+-activated K+ (KCa2.X or SK) channels [1].

Literature references

  1. de Vrind V, Scuvee-Moreau J, Drion G, Hmaied C, Philippart F, Engel D, Seutin V;, Eur J Pharmacol. 2016;788:274-279.: Interactions between calcium channels and SK channels in midbrain dopamine neurons and their impact on pacemaker regularity: Contrasting roles of N- and L-type channels. PUBMED:27364758 EPMC:27364758

  2. Silva J, Monge-Fuentes V, Gomes F, Lopes K, dos Anjos L, Campos G, Arenas C, Biolchi A, Goncalves J, Galante P, Campos L, Mortari M;, Toxins (Basel). 2015;7:3179-3209.: Pharmacological Alternatives for the Treatment of Neurodegenerative Disorders: Wasp and Bee Venoms and Their Components as New Neuroactive Tools. PUBMED:26295258 EPMC:26295258

  3. Hider RC, Ragnarsson U;, Biochim Biophys Acta. 1981;667:197-208.: A comparative structural study of apamin and related bee venom peptides. PUBMED:7213796 EPMC:7213796


This tab holds annotation information from the InterPro database.

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Domain organisation

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Alignments

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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

  Seed
(3)
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(5)
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(8)
NCBI
(12)
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(5)
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RP75
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Format an alignment

  Seed
(3)
Full
(5)
Representative proteomes UniProt
(8)
NCBI
(12)
Meta
(0)
RP15
(5)
RP35
(5)
RP55
(5)
RP75
(5)
Alignment:
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  Seed
(3)
Full
(5)
Representative proteomes UniProt
(8)
NCBI
(12)
Meta
(0)
RP15
(5)
RP35
(5)
RP55
(5)
RP75
(5)
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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

This family is new in this Pfam release.

Seed source: PRODOM:PD026566
Previous IDs: none
Type: Family
Author: El-Gebali S
Number in seed: 3
Number in full: 5
Average length of the domain: 43.00 aa
Average identity of full alignment: 63 %
Average coverage of the sequence by the domain: 97.73 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 25.0 25.0
Trusted cut-off 38.7 38.7
Noise cut-off 24.8 22.8
Model length: 49
Family (HMM) version: 1
Download: download the raw HMM for this family

Species distribution

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Archea Archea Eukaryota Eukaryota
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Viroids Viroids Unclassified sequence Unclassified sequence

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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Bee_toxin domain has been found. There are 1 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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