Mast cell degranulating (MCD)

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

is a

cation An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...

ic 22-

amino acid residue Protein structure is the three-dimensional arrangement of atoms in an amino acid-chain molecule. Proteins are polymers specifically polypeptides formed from sequences of amino acids, the monomers of the polymer. A single amino acid monomer may ...

peptide, which is a component of the venom of the

bumblebee A bumblebee (or bumble bee, bumble-bee, or humble-bee) is any of over 250 species in the genus ''Bombus'', part of Apidae, one of the bee families. This genus is the only extant group in the tribe Bombini, though a few extinct related gene ...

(''Megabombus pennsylvanicus''). At low concentrations, MCD peptide can stimulate

mast cell A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a pa ...

degranulation. At higher concentrations, it has anti-inflammatory properties. In addition, it is a potent blocker of voltage-sensitive

potassium channels Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of ce ...

Sources

MCD peptide is a component of

(''Megabombus pennsylvanicus'')

venom Venom or zootoxin is a type of toxin produced by an animal that is actively delivered through a wound by means of a bite, sting, or similar action. The toxin is delivered through a specially evolved ''venom apparatus'', such as fangs or a ...

. In addition to MCD peptide,

melittin Melittin is the main component (40–60% of the dry weight) and the major pain producing substance of honeybee (''Apis mellifera'') venom. Melittin is a basic peptide consisting of 26 amino acids. Function The principal function of melittin ...

and

apamin 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. ...

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 A honey bee (also spelled honeybee) is a eusocial flying insect within the genus ''Apis'' of the bee clade, all native to Afro-Eurasia. After bees spread naturally throughout Africa and Eurasia, humans became responsible for the current cosmop ...

Apis mellifera The western honey bee or European honey bee (''Apis mellifera'') is the most common of the 7–12 species of honey bees worldwide. The genus name ''Apis'' is Latin for "bee", and ''mellifera'' is the Latin for "honey-bearing" or "honey carrying", ...

''.

Chemistry

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

Targets

MCD peptide has

immunotoxic An immunotoxin is an artificial protein consisting of a targeting portion linked to a toxin. When the protein binds to that cell, it is taken in through endocytosis, and the toxin kills the cell. They are used for the treatment of some kinds of c ...

as well as

neurotoxic Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifical ...

properties due to different active sites of the MCD peptide. The MCD peptide has an immunotoxic effect on

mast cells A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granule (cell biology), granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the CFU-GEMM, ...

by releasing histamine from these cells. 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 Potassium voltage-gated channel subfamily A member 6 also known as Kv1.6 is a protein that in humans is encoded by the ''KCNA6'' gene. The protein encoded by this gene is a voltage-gated potassium channel Voltage-gated potassium channels ...

, and less potently to

Kv1.2 Potassium voltage-gated channel subfamily A member 2 also known as Kv1.2 is a protein that in humans is encoded by the ''KCNA2'' gene. Function Potassium channels represent the most complex class of voltage-gated ion channels from both functi ...

. Accordingly, MCD peptide can act in various regions of rat brain, including cerebellum, brainstem, hypothalamus, striatum, midbrain, cortex, and hippocampus. However, MCD peptide shows no binding activity in the peripheral neuronal system.

Mode of action

For its immunotoxic properties, a low concentration of MCD peptide can cause mast cell degranulation by releasing

histamine Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered in ...

; at higher concentrations it displays anti-inflammatory activities. Through its effect on ionic channels, MCD peptide can induce

long term potentiation In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons ...

(LTP) in CA1 region of hippocampus. 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 A protein complex or multiprotein complex is a group of two or more associated polypeptide chains. Protein complexes are distinct from multienzyme complexes, in which multiple catalytic domains are found in a single polypeptide chain. Protein c ...

, consisting of polypeptide chains of molecular weight between 76,000-80,000 and 38,000 Daltons. By blocking potassium channels, the MCD peptide can increase the duration of action potentials and increase neuronal excitability.

Toxicity

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

hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over-reaction of the immune ...

reaction. 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 Voltage-gated potassium channels (VGKCs) are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized ce ...

by the MCD peptide. However, there is no toxicity of MCD administered peripherally, even at high doses.

Therapeutic use

As a mast cell activator, the MCD peptide evokes large increases in antigen-specific serum

immunoglobulin G Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG ...

( IgG) responses. Therefore, it is used as a vaccine adjuvant. MCD peptide analogs, such as

la12 La 1 (, ''The One'') is a Spanish free-to-air television channel owned and operated by Televisión Española (TVE), the television division of state-owned public broadcaster Radiotelevisión Española (RTVE). It is the corporation's flagship ...

MCD, provide a base for designing agents that can prevent IgE/Fc-RIa interactions and reduce allergic conditions.

References

{{Reflist Ion channel toxins Bumblebees