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.[2]
The principal function of melittin as a component of bee venom is to cause pain and destruction of tissue of intruders that threaten a beehive. However, in honey bees, melittin is not only expressed in the venom gland, but also in other tissues when infected with pathogens. The two venom molecules, melittin and secapin, that are over-expressed in honey bees infected with various pathogens, possibly indicate a role for melittin in the immune response of bees to infectious diseases.[3]
Structure
Melittin is a small peptide with no disulfide bridge; the N-terminal part of the molecule is predominantly hydrophobic and the C-terminal part is hydrophilic and strongly basic. In water, it forms a tetramer but it also can spontaneously integrate itself into cell membranes.[4]
Mechanism of action
Injection of melittin into animals and humans causes pain sensation. It has strong surface effects on cell membranes causing pore-formation in epithelial cells and the destruction of red blood cells. Melittin also activates nociceptor (pain receptor) cells through a variety of mechanisms.[2]
Melittin can open thermal nociceptor TRPV1 channels via cyclooxygenase metabolites resulting in depolarization of nociceptor cells. The pore forming effects in cells causes the release of pro-inflammatory cytokines. It also activates G-protein-coupled receptor-mediated opening of transient receptor potential channels. Finally melittin up-regulates the expression of Nav1.8 and Nav1.9 sodium channels in nociceptor cell causing long term action potential firing and pain sensation.[2]
Melittin is the main compound in bee venom, accounting for the potential lethality of a bee sting, which causes an anaphylactic reaction in some people.[5] At the sites of multiple stings, localized pain, swelling, and skin redness occur, and if bees are swallowed, life-threatening swelling of the throat and respiratory passages may develop.[5]
A mast cell 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 part of the immune and neuroimmune systems. Mast cells were discovered by Paul Ehrlich in 1877. Although best known for their role in allergy and anaphylaxis, mast cells play an important protective role as well, being intimately involved in wound healing, angiogenesis, immune tolerance, defense against pathogens, and vascular permeability in brain tumors.
A membrane transport protein is a membrane protein involved in the movement of ions, small molecules, and macromolecules, such as another protein, across a biological membrane. Transport proteins are integral transmembrane proteins; that is they exist permanently within and span the membrane across which they transport substances. The proteins may assist in the movement of substances by facilitated diffusion, active transport, osmosis, or reverse diffusion. The two main types of proteins involved in such transport are broadly categorized as either channels or carriers. Examples of channel/carrier proteins include the GLUT 1 uniporter, sodium channels, and potassium channels. The solute carriers and atypical SLCs are secondary active or facilitative transporters in humans. Collectively membrane transporters and channels are known as the transportome. Transportomes govern cellular influx and efflux of not only ions and nutrients but drugs as well.
Bradykinin (BK) (from Greek brady- 'slow' + -kinin, kīn(eîn) 'to move') is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor and makes veins constrict, via prostaglandin F2, thereby leading to leakage into capillary beds, due to the increased pressure in the capillaries. Bradykinin consists of nine amino acids, and is a physiologically and pharmacologically active peptide of the kinin group of proteins.
Apitoxin or bee venom is the venom produced by the honey bee. It is a cytotoxic and hemotoxic bitter colorless liquid containing proteins, which may produce local inflammation. It may have similarities to sea nettle toxin.
Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed mainly by cells of the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils, as well as by epithelial cells, to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with components of host's cells that are released during cell damage or death. They are also called primitive pattern recognition receptors because they evolved before other parts of the immune system, particularly before adaptive immunity. PRRs also mediate the initiation of antigen-specific adaptive immune response and release of inflammatory cytokines.
In cell biology, a phagosome is a vesicle formed around a particle engulfed by a phagocyte via phagocytosis. Professional phagocytes include macrophages, neutrophils, and dendritic cells (DCs).
Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels.
A bee sting is the wound and pain caused by the stinger of a female bee puncturing skin. Bee stings differ from insect bites, with the venom of stinging insects having considerable chemical variation. The reaction of a person to a bee sting may vary according to the bee species. While bee stinger venom is slightly acidic and causes only mild pain in most people, allergic reactions may occur in people with allergies to venom components.
The innate immune system or nonspecific immune system is one of the two main immunity strategies in vertebrates. The innate immune system is an alternate defense strategy and is the dominant immune system response found in plants, fungi, prokaryotes, and invertebrates.
A latrotoxin is a high-molecular mass neurotoxin found in the venom of spiders of the genus Latrodectus as well as at least one species of another genus in the same family, Steatoda nobilis. Latrotoxins are the main active components of the venom and are responsible for the symptoms of latrodectism.
Sodium voltage-gated channel alpha subunit 9 is a sodium ion channel that in humans is encoded by the SCN9A gene. It is usually expressed at high levels in two types of neurons: the nociceptive (pain) neurons at the dorsal root ganglion (DRG) and trigeminal ganglion; and sympathetic ganglion neurons, which are part of the autonomic (involuntary) nervous system.
Hemolysins or haemolysins are lipids and proteins that cause lysis of red blood cells by disrupting the cell membrane. Although the lytic activity of some microbe-derived hemolysins on red blood cells may be of great importance for nutrient acquisition, many hemolysins produced by pathogens do not cause significant destruction of red blood cells during infection. However, hemolysins are often capable of lysing red blood cells in vitro.
Sodium channel, voltage-gated, type XI, alpha subunit also known as SCN11A or Nav1.9 is a voltage-gated sodium ion channel protein which is encoded by the SCN11A gene on chromosome 3 in humans. Like Nav1.7 and Nav1.8, Nav1.9 plays a role in pain perception. This channel is largely expressed in small-diameter nociceptors of the dorsal root ganglion and trigeminal ganglion neurons, but is also found in intrinsic myenteric neurons.
Transient receptor potential cation channel subfamily V member 2 is a protein that in humans is encoded by the TRPV2 gene. TRPV2 is a nonspecific cation channel that is a part of the TRP channel family. This channel allows the cell to communicate with its extracellular environment through the transfer of ions, and responds to noxious temperatures greater than 52 °C. It has a structure similar to that of potassium channels, and has similar functions throughout multiple species; recent research has also shown multiple interactions in the human body.
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.
Mastoparan is a peptide toxin from wasp venom. It has the chemical structure Ile-Asn-Leu-Lys-Ala-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2.
Nav1.8 is a sodium ion channel subtype that in humans is encoded by the SCN10A gene.
Cell surface receptors are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving extracellular molecules. They are specialized integral membrane proteins that allow communication between the cell and the extracellular space. The extracellular molecules may be hormones, neurotransmitters, cytokines, growth factors, cell adhesion molecules, or nutrients; they react with the receptor to induce changes in the metabolism and activity of a cell. In the process of signal transduction, ligand binding affects a cascading chemical change through the cell membrane.
Acid-sensing ion channels (ASICs) are neuronal voltage-insensitive sodium channels activated by extracellular protons permeable to Na+. ASIC1 also shows low Ca2+ permeability. ASIC proteins are a subfamily of the ENaC/Deg superfamily of ion channels. These genes have splice variants that encode for several isoforms that are marked by a suffix. In mammals, acid-sensing ion channels (ASIC) are encoded by five genes that produce ASIC protein subunits: ASIC1, ASIC2, ASIC3, ASIC4, and ASIC5. Three of these protein subunits assemble to form the ASIC, which can combine into both homotrimeric and heterotrimeric channels typically found in both the central nervous system and peripheral nervous system. However, the most common ASICs are ASIC1a and ASIC1a/2a and ASIC3. ASIC2b is non-functional on its own but modulates channel activity when participating in heteromultimers and ASIC4 has no known function. On a broad scale, ASICs are potential drug targets due to their involvement in pathological states such as retinal damage, seizures, and ischemic brain injury.
Protoxin-I, also known as ProTx-I, or Beta/omega-theraphotoxin-Tp1a, is a 35-amino-acid peptide neurotoxin extracted from the venom of the tarantula Thrixopelma pruriens. Protoxin-I belongs to the inhibitory cystine knot (ICK) family of peptide toxins, which have been known to potently inhibit voltage-gated ion channels. Protoxin-I selectively blocks low voltage threshold T-type calcium channels, voltage gated sodium channels and the nociceptor cation channel TRPA1. Due to its unique ability to bind to TRPA1, Protoxin-I has been implicated as a valuable pharmacological reagent with potential applications in clinical contexts with regards to pain and inflammation
↑ Liu CC, Hao DJ, Zhang Q, An J, Zhao JJ, Chen B, Zhang LL, Yang H (2016). "Application of bee venom and its main constituent melittin for cancer treatment". Cancer Chemotherapy and Pharmacology. 78 (6): 1113–1130. doi:10.1007/s00280-016-3160-1. PMID27677623. S2CID12596298.
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