Mast Cell Degranulating Peptide

Mast Cell Degranulating Peptide Mark A. Simmons NEOUCOM, Rootstown, USA ã 2007 Elsevier Inc. All rights reserved.

Introduction Mast cell degranulating (MCD) peptide is cationic 22-amino acid residue peptide with two disulfide bridges derived from bee venom Breithaupt and Habermann (1968). MCD peptide derives its name from the fact that it causes mast cell degranulation and histamine release at low concentrations. Mast cell degranulating peptide binds to potassium channels located in specific areas of the human brain at the same site as does dendrotoxin. MCD peptide blocks potassium channels which leads to a prolongation of the neuronal action potential, increased central nervous system (CNS) excitability, and convulsions Mourre et al (1997).

Nomenclature Name of the Clinical Form Related NamesSource: EMTREE Chemical Names CAS Number

83856-13-7

Basic Chemistry Chemical Structure Structure

Comments Chemical Formula Properties Physical Properties Molecular Weight Solubility

Ile-Lys-Cys-Asn-Cys-Lys-Arg-His-Val-Ile-Lys-Pro-His-Ile-Cys-ArgLys-Ile-Cys-Gly-Lys-Asn Disulfide Bridges: 3-15; 5-19 C110H192N40O24S4

2588

Targets-Pharmacodynamics Mast cell degranulating peptide blocks voltage dependent potassium channels. 1

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Mast Cell Degranulating Peptide

Target Name(s): Kv1 voltage-gated potassium channel

Pre-Clinical Research Mast cell degranulating peptide has a variety of actions including release of histamine, antiinflammatory activity at higher concentrations Buku (1999), and blockade of ion channels. The peptide produces LTP in hippocampal neurons Cherubini et al (1987) and when injected into the brain leads to convulsions and neurodegeneration Mourre et al (1997). It has been frequently used in electrophysiological studies as a potassium channel blocker. Pharmacokinetics Potency

Value Units

Organ/ Tissue

Prep. and Route of Admin.

Cell Line/ Type

Effects

Exp. End Point Reference

Rat ED50 20

mM

ED50 37

nM

Nodose ganglion

Sensory A neurons

ED50 440

nM

Kv1.2 channels

Stably transfected B82 mouse fibroblasts

Human ED50 70

nM

Prostate

LNCaP cancer cell line

Block of potassium channels

Skyrma et al (1999)

Mouse ED50 185

nM

Fibroblasts

B82 cells

Werkman et al (1992)

ED50 490

nM

Kv1.1 channels

Stably transfected B82 mouse fibroblasts

Block of Kv1.2 potassium channel Block of peak K+ current

Frog ED50 33

nM

Myelinated sciatic nerve fibers

Brau et al (1990)

ED50 304

nM

Myelinated sciatic nerve fibers

ED50 99

nM

Myelinated sciatic nerve fibers

Block of delayed rectifier K+ current in normal Ringer solution Block of delayed rectifier K+ current in high K+ solution Block of slowly inactivating f1 component of K+ current in high K+ solution

Mast cells

Histamine release block of slowly inactivating K+ current Block of peak K+ current

Buku et al (1998) Stansfeld et al (1987) Grissmer et al (1994)

Grissmer et al (1994)

Brau et al (1990)

Brau et al (1990)

Comments

Mast Cell Degranulating Peptide ED50 7.6

mM

Myelinated sciatic nerve fibers

Block of rapidly inactivating f2 component of K+ current in high K+ solution

Brau et al (1990)

Other Research IC50 values for MCDP to compete with [125I]Kaliotoxin binding in various regions of the rat brain are shown in a paper by Bessone and colleagues Bessone et al (2004). Commercially available from Alomone Labs (http://www.alomone.com/System/ UpLoadFiles/DGallery/Docs/M-250.pdf) or Sigma-Aldrich (http://www.sigmaaldrich. com/cgi-bin/hsrun/Suite7/Suite/Suite.hjx;start=Suite.HsViewHierarchy.run?Detail=Product&ProductNumber=SIGMA-M8036&VersionSequence=1).

Journal Citations Breithaupt, H., Habermann, E., 1968. Mastcelldegranulierendes Peptid (MCDPeptid) aus Bienengift: isolierung, biochemische and pharmakologische Eigenschaften. Naunyn-Schmiedebergs. Arch. Pharmakol. Exp. Pathol., 261, 252–270. Mourre, C., Lazdunski, M., Jarrard, L.E., 1997. Behaviors and neurodegeneration induced by two blockers of K+ channels, the mast cell degranulating peptide and Dendrotoxin I. Brain Res., 762, 223–227. Cherubini, E., Ben Ari, Y., Gho, M., Bidard, J.N., Lazdunski, M., 1987. Long-term potentiation of synaptic transmission in the hippocampus induced by a bee venom peptide. Nature, 328(6125), 70–73. Buku, A., 1999. Mast cell degranulating (MCD) peptide: a prototypic peptide in allergy and inflammation. Peptides, 20(3), 415–420. Buku, A., Maulik, G., Hook, W.A., 1998. Bioactivities and secondary structure of mast cell degranulating (MCD) peptide analogs. Peptides, 19(1), 1–5. Stansfeld, C.E., Marsh, S.J., Parcej, D.N., Dolly, J.O., Brown, D.A., 1987. Mast cell degranulating peptide and dendrotoxin selectively inhibit a fast-activating potassium current and bind to common neuronal proteins. Neuroscience, 23(3), 893–902. Skryma, R., Van Coppenolle, F., Dufy-Barbe, L., Dufy, B., Prevarskaya, N., 1999. Characterization of Ca(2 +)-inhibited potassium channels in the LNCaP human prostate cancer cell line. Receptors Channels, 6(4), 241–253. Werkman, T.R., Kawamura, T., Yokoyama, S., Higashida, H., Rogawski, M.A., 1992. Charybdotoxin, dendrotoxin and mast cell degranulating peptide block the voltage-activated K+ current of fibroblast cells stably transfected with NGK1 (Kv1.2) K+ channel complementary DNA. Neuroscience, 50(4), 935–946. Grissmer, S., Nguyen, A.N., Aiyar, J., Hanson, D.C., Mather, R.J., Gutman, G.A., Karmilowicz, M.J., Auperin, D.D., Chandy, K.G., 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. Bessone, R., Martin-Eauclaire, M.F., Crest, M., Mourre, C., 2004. Heterogeneous competition of Kv1 channel toxins with kaliotoxin for binding in rat brain: autoradiographic analysis. Neurochem. Int., 45(7), 1039–1047. Brau, M.E., Dreyer, F., Jonas, P., Repp, H., Vogel, W., 1990. A K+ channel in Xenopus nerve fibres selectively blocked by bee and snake toxins: binding and voltage-clamp experiments. J. Physiol., 420, 365–385.

Further Reading Ziai, Russek, Wang, Beer, Blume, Mast cell degranulating peptide: a multi-functional neurotoxin, J. Pharm. Pharmacol., 42(7) (1990) 457–461.

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