Mast Cell Degranulating (MCD) Peptides、肥大細(xì)胞去顆粒（MCD）肽

Definition

Mast Cell Degranulating (MCD) peptide is a potent anti-inflammatory agent. At low concentrations, mediates the degranulation of mast cells thus evoking an inflammatory response. Also acts as a neurotoxin capable of blocking a class of voltage-gated potassium channels.

Discovery

This peptide is a basic, 22 amino acid residue component of honey bee venom with striking immunological and pharmacological activities. Mast cell degranulating peptide was initially introduced as a histamine releaser, by B. Fredholm in 1966 1, 2.

Structural Characteristics

The calculated structure of MCD-peptide is close to that proposed earlier for the homologues peptide tertiapin and is confirmed by NMR and CD data. MCD peptide has two disulfide bridges. In this first structure-activity study of MCD peptide, three analogs were synthesized and tested: two analogs shortened by omitting sequences 6-10 and 8-13, respectively, and one analog lacking the disulfide bridge between cysteine residues 5 and 19. These analogs were synthesized by solid-phase methods and were compared to MCD peptide in two assays for inflammation: histamine release from mast cells and superoxide anion release from neutrophils. All three analogs produced histamine release, although with only about one fifth of the activity of MCD peptide. Superoxide anion-releasing activity, however, did not parallel histamine release. MCD peptide did not release superoxide anion, while the 6-10 and 8-13 deletion analogs were strong and weak stimulants, respectively, of this anion. CD spectra showed that the secondary structures of the three analogs were very similar to that of MCD peptide, so that a change in secondary structure cannot completely explain the changes in releasing activities. Charge differences between the two deletion analogs and MCD peptide may explain some of the differences in activity. This was the first demonstration that the various activities of MCD peptide can be separated, and provides a lead through which the purported antiinflammatory activity of MCD peptide may possibly be explored 3.

Mode of Action

MCD, well known for its ability to release histamin from mast cells, is a rather harmless compound peripherally. However, intra ventricular injection increased the toxicity of MCD by four orders of magnitude. This central toxicity is not related to mast cell degranulation but to the presence of high-affinity binding sites for MCD in the brain. Apamin, which is another bee venom peptide and a blocker of Ca2+-gated K channels, had no effect on the binding of DTX, MCD, or f3-BTX despite a partial sequence overlap with MCD (causes mast cell degranulation and histamine release at low concentrations and has anti-inflammatory activity at higher concentrations. Because of these unique immunologic properties, MCD peptide may serve as a useful tool for studying secretory mechanisms of inflammatory cells such as mast cells, basophils, and leukocytes, leading to the design of compounds with therapeutic potential 4,5,6.

Functions

MCD produces in hippocampal slices LTP which is indistinguishable from that produced by a train of electrical stimulation (no change in postsynaptic cell properties, APV sensitive). In vivo push-pull experiments indicate that this LTP is not associated with a sustained enhancement of release of glutamate and aspartate, the two principle transmitters of the hippocampus, but there is a delayed enhanced release of proteins in the extracellular space which may contribute to the maintenance of the potentiation7.

MCD is also an epileptogenic neurotoxin, an avid blocker of the potassium channels and can cause a significant lowering of the blood pressure in rats. Some of the biological activities of MCD appear to have distinct mechanisms and may represent a good illustration of the structure-function relationship 8.Because of these unique immunologic properties, MCD peptide may serve as a useful tool for studying secretory mechanisms of inflammatory cells such as mast cells, basophils, and leukocytes, leading to the design of compounds with therapeutic potential 4.

References

1.Fredholm B (1966). Studies on a mast cell degranulating factor in bee venom. Biochem. Phannacol., 15(12):2037-2043.

2.Habermann E (1972). Bee and wasp venoms. Science., 177 (46):314-322.

3.Buku A, Reibman J, Pistelli A, Blandina P, Gazis D (1992). Mast cell degranulating (MCD) peptide analogs with reduced ring structure. J Protein Chem., 11(3):275-280.

4.Buku A (1999). Mast cell degranulating (MCD) peptide: a prototypic peptide in allergy and inflammation. Peptides., 20(3): 415-420.

5.Moczdlowski  E, Lucchesi K, Ravindra A (1988). An emerging pharmacology of peptide toxins targeted against potassium channels.J Membr. Biol., 105 (2):95-111.

6.Rehm H, Bidard JN, Schweitz H, Lazdunski M (1988). The receptor site for the bee venom mast cell degranulating peptide. Biochem., 27(6):1827-1832.

7.Ben AY, Cherubini E, Aniksztejn L, Roisin MP, Charriaut-Marlangue C (1989). Mechanism of induction of long term potentiation by the mast cell degranulating peptide. Pharmacopsychiatry,. 22(2):107-110.

8.Ziai MR, Russek S, Wang HC, Beer B, Blume AJ (1990). Mast cell degranulating peptide: a multi-functional neurotoxin. J Pharm Pharmacol., 42(7):457-461.