MCD peptide

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.

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)

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]

References
  1. 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. 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. 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. 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. 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. 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. 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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