G protein receptor

G protein-coupled receptors (GPCRs), also known as seven transmembrane domain receptors, 7TM receptors, heptahelical receptors, and G protein-linked receptors (GPLR), comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal transduction pathways and, ultimately, cellular responses. G protein-coupled receptors are found only in eukaryotes, including yeast, plants, choanoflagellates, and animals. The ligands that bind and activate these receptors include light-sensitive compounds, odors, pheromones, hormones, and neurotransmitters, and vary in size from small molecules to peptides to large proteins. G protein-coupled receptors are involved in many diseases, but are also the target of around half of all modern medicinal drugs

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These proteins receive chemical signals from outside the cell and pass the signal into the cell, so that the cell can respond to the signal. The structures of the endogenous ligands for GPCRs are exceptionally diverse. They include biogenic amines such as norephnephrine and serotonine, peptides, glycoproteins, lipids, nucleotides, ions, and proteases. The sensation of exogenous stimuli, such as light, odors, and taste, is also mediated by this class of receptors. Activation of the receptor causes an effector inside the cell to produce a second signal chemical, which eventually triggers the cell to react to the original external chemical signal.

A ligand, in this case Norepinepherine (NE), binds to the receptor and induces a conformational change. This conformational change activates the a/b complex. The complex is bound to GDP while it is inactive. GTP replaces GDP, thus activating the Alpha subunit. The activated Alpha subunit undergoes a conformational change and activates Adenylate Cyclase. Once the Adenylate Cyclase is activated, it is then able to convert ATP. The products of ATP conversion are c-AMP and two phosphate molecules. c-AMP is a second messenger used in many processes required for cell survival and growth.

Cadherins Animation

Cadherins mediate cell adhesion and play a fundamental role in normal development. They participate in the maintenance of proper cell-cell contacts. Cadherins typically consist of five tandem repeated extracellular domains, a single membrane-spaning segment and a cytoplasmic region. Cadherins depend on calcium for their function: removal of calcium abolishes adhesive activity and renders cadherins vunerable to proteases.

FUNCTION

Cadherins generally mediate monotypic cell-cell adhesion although heterotypic binding between different cadherin molecules is possible. They act as both receptor and ligand. They are responsible for the selective cell-cell adhesion or cell sorting which is necessary to allocate different cell types to their proper positions during development. They also play a fundamental role in maintaining the integrity of multicellular structures. During embryonic morphogenesis, the expression of multiple members of the cadherin family is spatio-temporally regulated, and correlates with a variety of morphogenetic events that involve cell aggregation or disaggregation.

The role of cadherins in these processes has been demonstrated by the use of anti-cadherin monoclonal antibodies, which, when added to embyonic tissues, cause a severe distortion of structure which results in dissociation of the tissue into small clusters or even single cells.

STRUCTURE

The cadherins are synthesized as a precursor polypeptide which requires a series of post-translational modifications (glycosylation, phosphorylation and proteolytic cleavage) to form a protein which is between 723 and 748 amino acids long. The extracelluar domain contains 3-5 internal repeats of approximately 110 amino acids. Repeats 1-3 contain the putative Ca2+ binding site motif DXNDN or DXD, resembling the Ca2+ binding lops of the so-called EF-hand domains. Another high conserved cluster with the motif LDREXXXXYXL is also found with the first three repeats.

The N-terminal 113 amino acids which contain a conserved HAV sequence have been shown to be important in ligand binding and specificity. The extracellular domain is anchored to the cell membrane by a transmembrance domain of approximately 24 amino acids. The short cytoplasmic domain is the most highly conserved region of homology between cadherins and is particularly important for cadherin function

REGULATION OF EXPRESSION AND SIGNAL TRANSDUCTION

Cadherins are differentially expressed during development and in adult organs. Since many cell types express multiple cadherin subclasses simultaneously (the combination differs with cell type), it can be inferred that the adhesion properities of individual cells are thus governed by varying the combinations of cadherins. There is also recent evidence to suggest that altered expression of cadherins may be involved in invasion and metastasis of tumour cells.
On the cell surface, cadherins tend to be concentrated at cell-cell junctions. Here they are structurally associated with cortical actin bundles. The cytoplasmic domain has been shown to be associated with cytoplasmic proteins termed catenins. Deletion of the cytoplasmic domain destroys these interactions and also eliminates cadherin function. Recently src, yes, and lyn gene products of the src proto-oncogene family have been found expressed at cell-cell junctions. These kinases may be responsible for cadherin phosphorylation and this raises the possibly that cadherin mediated cell junctions might be used for intercellular signalling

Cell Signals Animation

Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue homeostasis. Errors in cellular information processing are responsible for diseases such as cancer, autoimmunity, and diabetes. By understanding cell signaling, diseases can be treated effectively and, theoretically, artificial tissues could be built.

Traditional work in biology has focused on studying individual parts of cell signaling pathways. Systems biology research helps us understand the underlying structure of cell signaling networks and how changes in these networks can affect the transmission of information.



Cell signaling has been most extensively studied in the context of human diseases and signaling between cells of a single organism. However, cell signaling can also occur between the cells of two different organisms. In many mammals, early embryo cells exchange signals with cells of the uterus. In the human gastrointestinal tract, bacteria exchange signals with each other and with human epithelial and immune system cells. For the yeast Saccharomyces cerevisiae during mating, some cells send a peptide signal (mating factor) into their environment. The mating factor peptide can bind to a cell surface receptor on other yeast cells and induce them to prepare for mating.

Some cell-to-cell communication requires direct cell-cell contact. Some cells can form gap junctions that connect their cytoplasm to the cytoplasm of adjacent cells. In cardiac muscle, gap junctions between adjacent cells allows for action potential propagation from the cardiac pacemaker region of the heart to spread and coordinately cause contraction of the heart.

The Notch signaling mechanism is an example of juxtacrine signalling in which two adjacent cells must make physical contact in order to communicate. This requirement for direct contact allows for very precise control of cell differentiation during embryonic development. In the worm Caenorhabditis elegans, two cells of the developing gonad each have an equal chance of terminally differentiating or becoming a uterine precursor cell that continues to divide. The choice of which cell continues to divide is controlled by competition of cell surface signals. One cell will happen to produce more of a cell surface protein that activates the Notch receptor on the adjacent cell. This activates a feedback system that reduces Notch expression in the cell that will differentiate and increases Notch on the surface of the cell that continues as a stem cell.

Many cell signals are carried by molecules that are released by one cell and move to make contact with another cell. Endocrine signals are called hormones. Hormones are produced by endocrine cells and they travel through the blood to reach all parts of the body. Specificity of signaling can be controlled if only some cells can respond to a particular hormone. Paracrine signals target only cells in the vicinity of the emitting cell. Neurotransmitters represent an example. Some signaling molecules can function as both a hormone and a neurotransmitter. For example, epinephrine and norepinephrine can function as hormones when released from the adrenal gland and are transported to the heart by way of the blood stream. Norepinephrine can also be produced by neurons to function as a neurotransmitter within the brain. Estrogen can be released by the ovary and function as a hormone or act locally via paracrine or autocrine signaling.