MCD peptide

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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 properties. In addition, it is a potent blocker of voltage-sensitive potassium channels.

Contents

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 and 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]

Related Research Articles

Taicatoxin (TCX) is a snake toxin that blocks voltage-dependent L-type calcium channels and small conductance Ca2+-activated K+ channels. The name taicatoxin (TAIpan + CAlcium + TOXIN) is derived from its natural source, the taipan snake, the site of its action, calcium channels, and from its function as a toxin. Taicatoxin was isolated from the venom of Australian taipan snake, Oxyuranus scutellatus scutellatus. TCX is a secreted protein, produced in the venom gland of the snake.

<span class="mw-page-title-main">Maurotoxin</span> Toxin in scorpions

Maurotoxin is a peptide toxin from the venom of the Tunisian chactoid scorpion Scorpio maurus palmatus, from which it was first isolated and from which the chemical gets its name. It acts by blocking several types of voltage-gated potassium channel.

<span class="mw-page-title-main">Margatoxin</span>

Margatoxin (MgTX) is a peptide that selectively inhibits Kv1.3 voltage-dependent potassium channels. It is found in the venom of Centruroides margaritatus, also known as the Central American Bark Scorpion. Margatoxin was first discovered in 1993. It was purified from scorpion venom and its amino acid sequence was determined.

<span class="mw-page-title-main">Apamin</span> Chemical compound

Apamin is an 18 amino acid globular peptide neurotoxin found in apitoxin (bee venom). Dry bee venom consists of 2–3% of apamin. 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, in particular 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.

<span class="mw-page-title-main">KCNA5</span> Protein-coding gene in humans

Potassium voltage-gated channel, shaker-related subfamily, member 5, also known as KCNA5 or Kv1.5, is a protein that in humans is encoded by the KCNA5 gene.

<span class="mw-page-title-main">KCNA3</span> Protein-coding gene in the species Homo sapiens

Potassium voltage-gated channel, shaker-related subfamily, member 3, also known as KCNA3 or Kv1.3, is a protein that in humans is encoded by the KCNA3 gene.

<span class="mw-page-title-main">KCNA7</span> Protein-coding gene in the species Homo sapiens

Potassium voltage-gated channel subfamily A member 7 also known as Kv1.7 is a protein that in humans is encoded by the KCNA7 gene. The protein encoded by this gene is a voltage-gated potassium channel subunit. It may contribute to the cardiac transient outward potassium current (Ito1), the main contributing current to the repolarizing phase 1 of the cardiac action potential.

<span class="mw-page-title-main">Heteroscodratoxin-1</span>

Heteroscodratoxin-1 is a neurotoxin produced by the venom glands of Heteroscodra maculata that shifts the activation threshold of voltage-gated potassium channels and the inactivation of Nav1.1 sodium channels to more positive potentials.

Parabutoxin (PBTx) is a Shaker-related voltage-gated K+ channel (Kvα1) inhibitor purified from different Parabuthus scorpion species found in southern Africa. It occurs in different forms: parabutoxin 1 (PBTx1), parabutoxin 2 (PBTx2), parabutoxin 3 (PBTx3) and parabutoxin (PBTx10). The different variants have different affinities towards Kvα1 channels.

Anuroctoxin is a peptide from the venom of the Mexican scorpion Anuroctonus phaiodactylus. This neurotoxin belongs to the alpha family of potassium channel acting peptides. It is a high-affinity blocker of Kv1.3 channels.

Ergtoxin is a toxin from the venom of the Mexican scorpion Centruroides noxius. This toxin targets hERG potassium channels.

<span class="mw-page-title-main">Pandinus imperator (Pi3) toxin</span>

Pi3 toxin is a purified peptide derivative of the Pandinus imperator scorpion venom. It is a potent blocker of voltage-gated potassium channel, Kv1.3 and is closely related to another peptide found in the venom, Pi2.

Tamulotoxin is a venomous neurotoxin from the Indian Red Scorpion.

Kaliseptine (AsKS) is a neurotoxin which can be found in the snakelocks anemone Anemonia viridis. It belongs to a class of sea anemone neurotoxins that inhibits voltage-gated potassium channels.

HsTx1 is a toxin from the venom of the scorpion Heterometrus spinifer. HsTx1 is a very potent inhibitor of the rat Kv1.3 voltage-gated potassium channel.

Pi4 is a short toxin from the scorpion Pandinus imperator that blocks specific potassium channels.

BmP02, also known as α-KTx 9.1 or Bmkk(6), is a toxin from the Buthus Martensi Karsch (BmK) scorpion. The toxin acts on potassium channels, blocking Kv1.3 and slowing the deactivation of Kv4.2. BmP02 is not toxic to humans or mice.

<span class="mw-page-title-main">OdK2</span>

OdK2 is a toxin found in the venom of the Iranian scorpion Odonthobuthus doriae. It belongs to the α-KTx family, and selectively blocks the voltage-gated potassium channel Kv1.3 (KCNA3).

<span class="mw-page-title-main">OSK3</span>

OSK3, from the venom of the scorpion Orthochirus scrobiculosus, is a potassium channel blocker that belongs to the α-KTx8 subfamily and targets the voltage-gated potassium channels KCNA2 (Kv1.2), and KCNA3 (Kv1.3).

AsKC11 is a toxin found in the venom of the sea anemone, Anemonia sulcata. This toxin is part of the Kunitz peptide family and has been shown to be an activator of G protein-coupled inwardly-rectifying potassium (GIRK) channels 1/2, involved in the regulation of cellular excitability. 

References

  1. 1 2 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. S2CID   3858397.
  2. 1 2 Breithaupt, H; Habermann, E (1968). "Mastzelldegranulierendes Peptid (MCD-Peptid) aus Bienengift: Isolierung, biochemische und pharmakologische Eigenschaften". Naunyn-Schmiedebergs Arch. Pharmakol. Exp. Pathol. 261 (3): 252–270. doi:10.1007/BF00536989. S2CID   43037442.
  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. S2CID   23838583.
  4. 1 2 3 4 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. S2CID   20534216.
  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. 1 2 3 4 5 Dreyer, F (1990). "Peptide Toxins and potassium channels". Rev. Physiol. Biochem. Pharmacol. 115: 93–136. PMID   2183333.
  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. S2CID   30941704.
  8. ↑ Pongs, O (1992). "Molecular biology of voltage-dependent potassium channels". Physiol. Rev. 72 (4 Suppl): 69–88. doi:10.1152/physrev.1992.72.suppl_4.S69. PMID   1438587.
  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. doi:10.1002/j.1460-2075.1989.tb08483.x. PMC   401447 . PMID   2555158.
  12. 1 2 3 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. doi: 10.1016/S0021-9258(18)89838-6 . PMID   6501283.
  13. 1 2 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. Bibcode:1987Natur.328...70C. doi:10.1038/328070a0. PMID   2885754. S2CID   4338101.
  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. Bibcode:1988PNAS...85.4919R. doi: 10.1073/pnas.85.13.4919 . PMC   280549 . PMID   2455300.
  15. 1 2 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. S2CID   28729760.
  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". Journal of Peptide Research. 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. S2CID   2702116.
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