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Integrins are cell surface receptors that interact with the extracellular matrix (ECM) and mediate various intracellular signals. In Biochemistry, a receptor is a Protein molecule embedded in either the Plasma membrane or Cytoplasm of a cell to which a mobile signaling In Biology, the extracellular matrix ( ECM) is the Extracellular part of animal tissue that usually provides structural support to the cells Cell signaling is part of a Complex system of Communication that governs basic cellular activities and coordinates cell actions They define cellular shape, mobility, and regulate the cell cycle. The cell cycle, or cell-division cycle, is the series of events that take place in a eukaryotic cell leading to its replication These integral membrane proteins are attached to the cellular plasma membrane through a single transmembrane helix. An Integral Membrane Protein ( IMP) is a Protein Molecule (or assembly of proteins that is permanently attached to the Biological membrane. The cell membrane (also called the plasma membrane, plasmalemma, or "phospholipid bilayer" is a Selectively permeable Lipid bilayer Transmembrane domain usually denotes a single transmembrane Alpha helix of a Transmembrane protein.

Integrin plays a role in the attachment of cells to other cells, and also plays a role in the attachment of a cell to the material part of a tissue that is not part of any cell (the extracellular matrix). In Biology, the extracellular matrix ( ECM) is the Extracellular part of animal tissue that usually provides structural support to the cells Besides the attachment role, integrin also plays a role in signal transduction, a process by which a cell transforms one kind of signal or stimulus into another. In Biology, signal transduction refers to any process by which a cell converts one kind of signal or stimulus into another

The integrins are unusual membrane proteins because the signals they convert travel in both outside-in: transducing information from the ECM to the cell, and inside-out: "revealing" the status of the cell to the extracellular world. This allows cells to make rapid and flexible responses (see the example of platelets, in the Function section). It is more common for cells to make new receptors on their surfaces, or remove them if they need to alter their ability to respond to the environment.

There are many types of integrin, and many cells have multiple types on their surface. Integrins are of vital importance to all animals and have been found in all animals tested, from sponges to mammals. The sponges or poriferans (from Latin porus "pore" and ferre "to bear" are Animals Mammals ( class Mammalia) are a class of Vertebrate Animals characterized by the presence of Sweat glands, including sweat glands Integrins have been extensively studied in humans.

Other types of protein that play a role in cell-cell and cell-matrix interaction and communication are cadherins, CAMs and selectins. Proteins are large Organic compounds made of Amino acids arranged in a linear chain and joined together by Peptide bonds between the Carboxyl Cadherins are a class of type-1 Transmembrane proteins They play important roles in Cell adhesion, ensuring that cells within tissues are bound together Cell Adhesion Molecules ( CAM s are Proteins located on the cell surface involved with the Binding with other cells or with the Extracellular Selectins are a family of cell adhesion Molecules (or CAMs. All selectins are single-chain transmembrane Glycoproteins that share similar properties

Contents

Structure

Integrins are obligate heterodimers containing two distinct chains, called the α (alpha) and β (beta) subunits. A dimer is a Chemical or Biological entity consisting of two subunits called Monomers which are held together by either Intramolecular forces In mammals, 19 α and 8 β subunits have been characterized, whereas the Drosophila and Caenorhabditis genomes encode only five α and two β subunits. Mammals ( class Mammalia) are a class of Vertebrate Animals characterized by the presence of Sweat glands, including sweat glands Drosophila is a Genus of small flies, belonging to the family Drosophilidae, whose members are often called "fruit flies" This genus contains the noted Model organism Caenorhabditis elegans and several other species for which a Genome sequence is either available or currently In classical genetics the genome of a Diploid Organism including Eukarya refers to a full set of chromosomes or genes in a Gamete, thereby [1]

In addition, variants of some of the subunits are formed by differential splicing, for example 4 variants of the beta-1 subunit exist. CD49a is an Integrin alpha subunit It makes up half of the α1β1 integrin duplex CD49b (also known as DX5) is an Integrin alpha subunit It makes up half of the α2β1 integrin duplex Integrin alpha 2b (platelet glycoprotein IIb of IIb/IIIa complex antigen CD41, also known as ITGA2B, is a human Gene. Integrin alpha 3 (antigen CD49C alpha 3 subunit of VLA-3 receptor, also known as ITGA3 and CD49c, is a human Gene. CD49d is an Integrin alpha subunit It makes up half of the α4β1 lymphocyte homing receptor Integrin alpha 5 (fibronectin receptor alpha polypeptide, also known as ITGA5, is a human Gene. Integrin alpha 6, also known as ITGA6, is a human Gene. Integrin alpha E ( ITGAE) also known as CD103 ( C luster of D ifferentiation 103) is an Integrin. Integrin alpha L (antigen CD11A (p180 lymphocyte function-associated antigen 1 alpha polypeptide, also known as ITGAL, is a human Gene. Integrin alpha M (ITGAM is one protein subunit that forms the Heterodimeric Integrin alpha-M beta-2 (αMβ2 molecule also known as macrophage-1 Integrin alpha V (vitronectin receptor alpha polypeptide antigen CD51, also known as ITGAV, is a human Gene. CD11c, also known as Integrin alpha X (complement component 3 receptor 4 subunit ( ITGAX) is a human Gene. Integrin beta 1 (fibronectin receptor beta polypeptide antigen CD29 includes MDF2 MSK12, also known as ITGB1 or CD29, is a human Gene. Integrin beta 2 (complement component 3 receptor 3 and 4 subunit, also known as CD18 or ITGB2, is a human Gene. Integrin beta 3 (platelet glycoprotein IIIa antigen CD61, also known as ITGB3, is a human Gene. Through different combinations of these alpha and beta subunits, some 24 unique integrins are generated, although the number varies according to different studies. [2]

Integrin subunits span the plasma membrane and in general have very short cytoplasmic domains of about 40-70 amino acids. The cell membrane (also called the plasma membrane, plasmalemma, or "phospholipid bilayer" is a Selectively permeable Lipid bilayer In Chemistry, an amino acid is a Molecule containing both Amine and Carboxyl Functional groups In Biochemistry, this The exception is the beta-4 subunit which has a cytoplasmic domain of 1088 amino acids, one of the largest known cytoplasmic domains of any membrane protein. Outside the cell plasma membrane, the alpha and beta chains lie close together along a length of about 23nm, the final 5nm N-termini of each chain form a ligand-binding region for the ECM, or extracellular matrix. The cell membrane (also called the plasma membrane, plasmalemma, or "phospholipid bilayer" is a Selectively permeable Lipid bilayer A nanometre ( American spelling: nanometer, symbol nm) ( Greek: νάνος nanos dwarf; μετρώ metrό count) is a The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or In Biochemistry, a ligand ( latin ligare = to bind is a substance that is able to bind to and form a complex with a Biomolecule In Biology, the extracellular matrix ( ECM) is the Extracellular part of animal tissue that usually provides structural support to the cells

The molecular mass of the integrin subunits can vary from 90 kDa to 160 kDa. The molecular mass (abbreviated m of a substance, more commonly referred to as molecular weight and abbreviated as MW, is the Mass of one The unified atomic mass unit ( u) or Dalton ( Da) or sometimes universal mass unit, is an unit of Mass used to express β subunits have four cysteine-rich repeated sequences. Not to be confused with Cystine, its oxidized dimer Cysteine (abbreviated as Cys or C) is an α- Amino acid with Both α and β subunits bind several divalent cations. In chemistry divalent Anions are atoms or radicals with 2 additional Electrons when compared to their elemental state (that is with 2 more electrons than Protons An ion is an Atom or Molecule which has lost or gained one or more Valence electrons giving it a positive or negative electrical charge The role of the α cations is unknown, but they may stabilize the folds of the protein. The β cations are more interesting: they are directly involved in coordinating at least some of the ligands that integrins bind. In Biochemistry, a ligand ( latin ligare = to bind is a substance that is able to bind to and form a complex with a Biomolecule

There are various ways of categorizing the integrins. For example, a subset of the α chains has an additional structural element (or "domain") inserted toward their N-terminal, the so called alpha-A domain (because it has a similar structure to the A-domains found in the protein von Willebrand factor: it is also termed the α-I domain). The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or Von Willebrand factor (vWF is a Blood Glycoprotein involved in Hemostasis. Integrins carrying this domain either bind to collagens (e. Collagen is the main Protein of Connective tissue in Animals and the most abundant protein in Mammals making up about 50% of the whole-body protein g. integrins α1 β1, and α2 β1), or act as cell-cell adhesion molecules (integrins of the β2 family). The cell is the structural and functional unit of all known living Organisms It is the smallest unit of an organism that is classified as living and is often called This α-I domain is the binding site for ligands of such integrins. Those integrins that don't carry this inserted domain, also have an A-domain in their ligand binding site, but this A-domain is found on the β subunit.

In both cases, the A-domains carry up to three divalent cation binding sites. One is permanently occupied in physiological concentrations of divalent cations, and carries either a calcium or magnesium ion, the principal divalent cations in blood at median concentrations of 1. In Chemistry, concentration is the measure of how much of a given substance there is mixed with another substance 4 mM (calcium) and 0. 8 mM (magnesium). The other two sites become occupied by cations when ligands bind - at least for those ligands involving an acidic amino acid in their interaction sites. An acidic amino acid features in the integrin-interaction site of many ECM proteins, for example, as part of the amino acid sequence Arginine-Glycine-Aspartic acid ("RGD" in the one-letter aminoacid code). Arginine (abbreviated as Arg or R) is an α- Amino acid. The L-form is one of the 20 most common natural amino acids Glycine (abbreviated as Gly or G) is the Organic compound with the formula NH2CH2COOH Aspartic acid (abbreviated as Asp or D; Asx or B represent either aspartic acid or Asparagine) is an α- Amino acid

High resolution structure

Despite many years of effort, discovering the high resolution structure of integrins proved to be challenging: membrane proteins are classically difficult to purify, and integrins are also large, complex and linked to many sugar trees ("highly glycosylated"). Glycosylation is the enzymatic process that links Saccharides to produce glycans, either free or attached to Proteins and Lipids This enzymatic Low resolution images of detergent extracts of intact integrin GPIIbIIIa, obtained using electron microscopy, and even data from indirect techniques, investigating the solution properties of integrins using ultracentrifugation and light scattering, were combined with fragmentary high resolution crystallographic or NMR data from single or paired domains of single integrin chains, and molecular models postulated for the rest of the chains. Despite these wide-ranging efforts, the X-ray crystal structure obtained for the complete extracellular region of one integrin, αvβ3 was a surprise. X-radiation (composed of X-rays) is a form of Electromagnetic radiation. [3]

It showed the molecule to be folded into an inverted V-shape which brings the ligand-binding sites close to the cell membrane. Perhaps more importantly, the crystal structure was also obtained for the same integrin bound to a small ligand containing the RGD-sequence, the drug cilengitide. Cilengitide is a molecule designed and synthesized at the Technical University Munich in collaboration with Merck KGaA in Darmstadt [4] As detailed above, this finally revealed why divalent cations (in the A-domains) are critical for RGD-ligand binding to integrins. The interaction with such sequences is believed to be a primary switch by which ECM exerts its effects on cell behaviour.

The structure poses many questions, especially regarding ligand binding and signal transduction. The ligand binding site is directed towards the C-terminal of the integrin, the region where the molecule emerges from the cell membrane. If it emerges orthogonally from the membrane, the ligand binding site would apparently be obstructed, especially as integrin ligands are typically massive, and well cross-linked components of the ECM. In Mathematics, two Vectors are orthogonal if they are Perpendicular, i In fact, little is known about the angle which membrane proteins subtend to the plane of the membrane - it is a problem difficult to address with available technologies. The default assumption is that they emerge rather like little lollipops - the evidence for this sweet supposition is noticeable by its absence. The integrin structure has drawn attention to this problem, which may have implications for how membrane proteins work.

Although the crystal structure changed surprisingly little after binding to cilengitide, the current hypothesis is that integrin function involves changes in shape to move the ligand binding site into a more accessible position away from the cell surface, and this shape change also triggers intracellular signaling. And there is a wide body of cell biological and biochemical literature that supports this view. Perhaps the most convincing evidence involves the use of antibodies that only recognize integrins when they have bound to their ligands, or are activated. Antibodies (also known as immunoglobulins, abbreviated Ig) are Gamma globulin Proteins that are found in Blood or other Bodily As the "footprint" that an antibody makes on its binding target is roughly a circle about 3 nm in diameter, the resolution of this technique is low. Nevertheless, these so-called LIBS (Ligand-Induced-Binding-Sites) antibodies unequivocally show that dramatic changes in integrin shape routinely occur.

Function

Two main functions of integrins are:

However, they are also involved in a wide range of other biological activities. These include: binding of viruses, including adenovirus, Echo viruses, Hanta viruses and foot and mouth disease viruses, to cells; immune patrolling. Adenoviruses are medium-sized (90–100 nm) Nonenveloped (naked Icosahedral viruses composed of a nucleocapsid and a double-stranded linear DNA Foot-and-mouth disease ( FMD) or hoof-and-mouth disease ( Aphtae epizooticae) is a highly contagious and sometimes fatal viral Cell migration.

A very prominent function of the integrins is seen in the molecule GPIIbIIIa, an integrin on the surface of blood platelets (thrombocytes) responsible for cross-linking platelets in fibrin within a developing blood clot. This switches its adhesiveness for fibrin/fibrinogen from being non-adhesive to being intensely sticky, in a fast and precisely controlled manner. As such it provides a thought-model for how many integrins are believed to be regulated. As you may have noted, although blood is normally very rich in platelets, we do not spontaneously clot. This is clearly good news. On the other side, and equally positively, even minor wounds are rapidly blocked by the mass of fibrin, platelets and erythrocytes in a blood clot. A primary event in clot formation is the binding of platelets to exposed collagen in the wound site, which leads to their "activation", and a clotting cascade. Among the many molecular events during activation, is the switching of GPIIbIIIa integrin from a quiescent state, unable to bind to fibrinogen/fibrin, to an active state, able to bind strongly to fibrinogen/fibrin. This is a remarkable event: first it involves all the GPIIbIIIa on a single platelet (some 50000 molecules), second it is completed within 5 seconds, third, it increases the affinity of the integrin concerned over several orders of magnitude. Fourth, it involves wide spread changes in the molecular structure of the GPIIbIIIa molecule, as resolved by LIBS antibodies, which gain the ability to bind GPIIbIIIa only following activation of the platelets. Finally, it is intensely locallized to the precise region of the damage, be it a couple of square micrometres, or the results of falling off a mountain bike at high speed.

Attachment of cell to the ECM

Integrins couple the ECM outside a cell to the cytoskeleton (in particular the microfilaments) inside the cell. cytoskeleton (also CSK is a cellular " Scaffolding " or " Skeleton " contained within the Cytoplasm. Microfilaments (or actin filaments) are the thinnest filaments of the Cytoskeleton found in the cytoplasm of all Eukaryotic cells. Which ligand in the ECM the integrin can bind to is mainly decided by which α and β subunits the integrin is made of. Among the ligands of integrins are fibronectin, vitronectin, collagen, and laminin. In Chemistry, a ligand is either an Atom, Ion, or Molecule (see also Functional group) that bonds to a central metal generally Fibronectin is a high-molecular-weight extracellular matrix Glycoprotein containing about 5% Carbohydrate that binds to membrane spanning Receptor proteins Vitronectin is an abundant glycoprotein found in blood plasma and the Extracellular matrix. Collagen is the main Protein of Connective tissue in Animals and the most abundant protein in Mammals making up about 50% of the whole-body protein Laminin is the major non-collagenous component of the Basal lamina, such as those on which cells of an Epithelium sit The connection between the cell and the ECM may help the cell to endure pulling forces without being ripped out of the ECM. The ability of a cell to create this kind of bond is also of vital importance in ontogeny. Ontogeny, as opposed to Phylogeny, refers to the history of an organism from birth as opposed to its genetic makeup

Cell attachment to the ECM is a basic requirement to build a multicellular organism. Integrins are not simply hooks, but give the cell critical signals about the nature of its surroundings. Together with signals arising from receptors for soluble growth factors like VEGF, EGF and many others, they enforce a cellular decision on what biological action to take, be it attachment, movement, death, or differentiation. Vascular endothelial growth factor ( VEGF) a sub-family of Growth factors, more specifically of Platelet-derived growth factor family of cystine-knot growth Epidermal growth factor or EGF is a Growth factor that plays an important role in the regulation of Cell growth, Proliferation, and Thus integrins lie at the heart, both literally and figuratively, of many cellular biological processes. The attachment of the cell takes place through formation of cell adhesion complexes, which consist of integrins and many cytoplasmic proteins which include talin, vinculin, paxillin and alpha-actinin. Cellular adhesion is the binding of a cell to another cell or to a Surface or matrix. TALIN is a high-molecular-weight Cytoskeletal protein concentrated at regions of cell–substratum contact and in Lymphocytes, at cell–cell contacts In mammalian cells vinculin is a membrane-cytoskeletal protein in Focal adhesion plaques that is involved in linkage of Integrin adhesion molecules to the These act by regulating kinases like FAK (focal adhesion kinase) and Src kinase family members to phosphorylate substrates such as p130CAS thereby recruiting signaling adaptors such as Crk. In Chemistry and Biochemistry, a kinase, alternatively known as a phosphotransferase, is a type of Enzyme that transfers Phosphate Focal Adhesion Kinase ( FAK) is a focal adhesion-associated protein Kinase involved in cellular adhesion and spreading processes These adhesion complexes attach to the actin cytoskeleton. The integrins thus serve to link across the plasma membrane two networks: the extracellular ECM and the intracellular actin filamentous system.

One of the most important functions of surface integrins is their role in cell migration. Cell migration is a central process in the development and maintenance of Multicellular organisms Tissue formation during embryonic development, Wound healing Cells adhere to a substrate through their integrins. In Biology a substrate is the surface a plant or animal lives upon During movement, the cell makes new attachments to the substrate at its front and concurrently releases those at its rear. When released from the substrate, integrin molecules are taken back into the cell by endocytosis; they are transported through the cell to its front by the endocytic cycle where they are added back to the surface. Endocytosis is a process where cells absorb material ( Molecules such as proteins from the outside by engulfing it with their Cell membrane. Most animal cells take up portions of their surface Plasma membranes in a process called Endocytosis. In this way they are cycled for reuse, enabling the cell to make fresh attachments at its leading front.

Signal transduction

Integrins play an important role in cell signaling. Connection with ECM molecules can cause a signal to be relayed into the cell through protein kinases that are indirectly and temporarily connected with the intracellular end of the integrin molecule, likely following shape changes directly stimulated by ECM binding. In Chemistry and Biochemistry, a kinase, alternatively known as a phosphotransferase, is a type of Enzyme that transfers Phosphate

The signals the cell receives through the integrin can have relation to:

Vertebrate integrins

The following are some of the integrins found in vertebrates:

Name Synonyms Distribution Ligands
α1β1 Many Collagens, laminins. The term cell growth is used in two different ways in Biology. Cell division is a process by which a cell, called the parent cell divides into two or more cells called daughter cells. In Developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized Cell type. Collagen is the main Protein of Connective tissue in Animals and the most abundant protein in Mammals making up about 50% of the whole-body protein Laminin is the major non-collagenous component of the Basal lamina, such as those on which cells of an Epithelium sit [5]
α2β1 Many Collagens, laminins[5]
α4β1 VLA-4[5] Hematopoietic cells Fibronectin, VCAM-1[5]
α5β1 fibronectin receptor widespread fibronectin[5] and proteinases
α6β1 laminin receptor widespread matrix macromolecules laminins
αLβ2 LFA-1[5] T-lymphocytes ICAM-1, ICAM-2[5]
αMβ2 Mac-1, CR3[5] Neutrophils and monocytes Serum proteins, ICAM-1[5]
αIIbβ3 Platelets[5] fibrinogen, fibronectin[5]
αVβ3 vitronectin receptor[6] activated endothelial cells, melanoma, glioblastoma vitronectin [6], fibronectin, fibrinogen, osteopontin, Cyr61
αVβ5 widespread, esp. Integrin alpha4beta1 ( Very Late Antigen-4) is an Integrin Dimer. Haematopoiesis (from Ancient Greek haima blood poiesis to make (or hematopoiesis in the United States sometimes also haemopoiesis or Fibronectin is a high-molecular-weight extracellular matrix Glycoprotein containing about 5% Carbohydrate that binds to membrane spanning Receptor proteins Vascular cell adhesion molecule 1, also known as VCAM1, is a human Gene. α5β1 is an Integrin that binds to Matrix macromolecules and Proteinases and thereby stimulates Angiogenesis. A protease is any Enzyme that conducts Proteolysis, that is begins protein Catabolism by Hydrolysis of the Peptide bonds that link In Biology, the extracellular matrix ( ECM) is the Extracellular part of animal tissue that usually provides structural support to the cells LFA-1 stands for Lymphocyte function-associated antigen-1 LFA-1 is found on all T-cells and also on B-cells, Macrophages and Neutrophils T cells belong to a group of White blood cells known as Lymphocytes, and play a central role in Cell-mediated immunity. Cell adhesion molecule ICAM-1 (Inter-Cellular Adhesion Molecule 1 also known as CD54 ( C luster of D ifferentiation 54 is a human Gene. Intercellular adhesion molecules are members of the family of Cell adhesion molecules They include the following ICAM-1 (see also CD54 Macrophage-1 antigen (or integrin alphaMbeta2) is a Complement receptor ("CR3" consisting of CD11b and CD18. Neutrophil granulocytes, generally referred to as neutrophils, are the most abundant type of White blood cells in humans and form an essential part of the Monocyte is a type of Leukocyte, part of the Human body 's Immune system. Platelets, or Thrombocytes, are small cytoplasmic bodies derived from cells They circulate in the Blood of Mammals and are involved αVβ3 is a type of Integrin that is a receptor for Vitronectin. Vitronectin is an abundant glycoprotein found in blood plasma and the Extracellular matrix. αVβ5 is a type of Integrin that binds to Matrix macromolecules and Proteinases and thereby stimulates Angiogenesis. fibroblasts, epithelial cells vitronectin and adenovirus
αVβ6 proliferating epithelia, esp. Vitronectin is an abundant glycoprotein found in blood plasma and the Extracellular matrix. lung and liver fibronectin; TGFβ1+3
α6β4 Epithelial cells[5] Laminin[5]

Beta1 integrins interact with many alpha integrin chains. Fibronectin is a high-molecular-weight extracellular matrix Glycoprotein containing about 5% Carbohydrate that binds to membrane spanning Receptor proteins In biology and medicine epithelium is a tissue composed of cells that line the cavities and surfaces of structures throughout the body Laminin is the major non-collagenous component of the Basal lamina, such as those on which cells of an Epithelium sit Gene knockouts of integrins in mice are not always lethal. It proves that during embryonal development, one integrin may substitute its function for another, to allow survival. Some integrins are on the cell surface in an inactive state, and can be rapidly primed, or put into a state capable of binding their ligands, by cytokines. Integrins can assume several different well defined shapes, or "conformational states". Once primed, the conformational state changes to stimulate ligand binding which then activates the receptors, also by inducing a shape change, to trigger outside-in signal transduction.

Additional images

Integrin (captions in German)

References

  1. ^ Humphries M. J. (2000). "Integrin structure". Biochem. Soc. Trans. 28 (4): 311-339. doi:10.1042/0300-5127:0280311. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 10961914.  
  2. ^ Hynes R (2002). "Integrins: bidirectional, allosteric signaling machines". Cell 110 (6): 673-87. doi:10.1016/S0092-8674(02)00971-6. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 12297042.  
  3. ^ Xiong JP (2001). "Crystal structure of the extracellular segment of integrin αvβ3". Science 294 (5541): 339-345. doi:10.1126/science.1064535. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 11546839.  
  4. ^ Smith J (2003). "Cilengitide Merck". Curr Opin Investig Drugs 4 (6): 741-5. PMID 12901235.  
  5. ^ a b c d e f g h i j k l m Molecular cell biology. Lodish, Harvey F. 5. ed.  : - New York : W. H. Freeman and Co. , 2003, 973 s. b ill. ISBN 0-7167-4366-3
  6. ^ a b PMID: 10037797

External links

Medical Subject Headings ( MeSH) is a huge Controlled vocabulary (or metadata system for the purpose of indexing journal articles and books

Dictionary

integrin

-noun

  1. (biochemistry) Any of many heterodimeric transmembrane proteins that function as receptors in communication between cells.
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