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In biology, cell signaling ( cell signalling in British English) is the process by which a cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all cellular life in both and . Typically, the signaling process involves three components: the first messenger (the ligand), the receptor, and the signal itself.
In biology, signals are mostly chemical in nature, but can also be physical cues such as pressure, voltage, temperature, or light. Chemical signals are molecules with the ability to bind and activate a specific receptor. These molecules, also referred to as ligands, are chemically diverse, including (e.g. Na+, K+, Ca2+, etc.), lipids (e.g. steroid, prostaglandin), peptides (e.g. insulin, ACTH), carbohydrates, glycosylated proteins (proteoglycans), nucleic acids, etc. Peptide and lipid ligands are particularly important, as most hormones belong to these classes of chemicals. Peptides are usually polar, hydrophilic molecules. As such they are unable to diffuse freely across the bi-lipid layer of the plasma membrane, so their action is mediated by a cell membrane bound receptor. On the other hand, liposoluble chemicals such as steroid hormones, can diffuse passively across the plasma membrane and interact with intracellular receptors.
Cell signaling can occur over short or long distances,and can be further classified as autocrine, intracrine, juxtacrine, paracrine, or endocrine. Autocrine signaling occurs when the chemical signal acts on the same cell that produced the signaling chemical. Intracrine signaling occurs when the chemical signal produced by a cell acts on receptors located in the cytoplasm or nucleus of the same cell. Juxtacrine signaling occurs between physically adjacent cells. (2025). 9780878932436, Sinauer Assoc. ISBN 9780878932436 Paracrine signaling occurs between nearby cells. Endocrine interaction occurs between distant cells, with the chemical signal usually carried by the blood.
Receptors are complex proteins or tightly bound multimer of proteins, located in the plasma membrane or within the interior of the cell such as in the cytoplasm, , and Cell nucleus. Receptors have the ability to detect a signal either by binding to a specific chemical or by undergoing a conformational change when interacting with physical agents. It is the specificity of the chemical interaction between a given ligand and its receptor that confers the ability to trigger a specific cellular response. Receptors can be broadly classified into cell membrane receptors and intracellular receptors. Cell membrane receptors can be further classified into ion channel linked receptors, G-Protein coupled receptors and enzyme linked receptors.
Intracellular receptors have a different mechanism of action. They usually bind to lipid soluble ligands that diffuse passively through the plasma membrane such as steroid hormones. These ligands bind to specific cytoplasmic transporters that shuttle the hormone-transporter complex inside the nucleus where specific genes are activated and the synthesis of specific proteins is promoted.
The effector component of the signaling pathway begins with signal transduction. In this process, the signal, by interacting with the receptor, starts a series of molecular events within the cell leading to the final effect of the signaling process. Typically the final effect consists in the activation of an ion channel (ligand-gated ion channel) or the initiation of a second messenger system cascade that propagates the signal through the cell. Second messenger systems can amplify or modulate a signal, in which activation of a few receptors results in multiple secondary messengers being activated, thereby amplifying the initial signal (the first messenger). The downstream effects of these signaling pathways may include additional enzymatic activities such as Protease, phosphorylation, methylation, and ubiquitinylation.
Signaling molecules can be synthesized from various biosynthetic pathways and released through passive or , or even from cell damage.
Each cell is programmed to respond to specific extracellular signal molecules, and is the basis of development, tissue repair, immunity, and homeostasis. Errors in signaling interactions may cause diseases such as cancer, autoimmunity, and diabetes.
In , individual cells aggregate together to form fruiting bodies and eventually spores, under the influence of a chemical signal, known as an acrasin. The individuals move by chemotaxis, i.e. they are attracted by the chemical gradient. Some species use cyclic AMP as the signal; others such as Polysphondylium violaceum use a dipeptide known as glorin.
In plants and animals, signaling between cells occurs either through release into the extracellular space, divided in paracrine signaling (over short distances) and endocrine signaling (over long distances), or by direct contact, known as juxtacrine signaling such as notch signaling. Autocrine signaling is a special case of paracrine signaling where the secreting cell has the ability to respond to the secreted signaling molecule. Synapse signaling is a special case of paracrine signaling (for ) or juxtacrine signaling (for electrical synapses) between and target cells.
In the context of neurotransmission, neurotransmitters are typically released from into the synaptic cleft via exocytosis; however, neurotransmitters can also be released via reverse transport through membrane transport proteins.
Additionally, in unicellular organisms such as bacteria, juxtacrine signaling means interactions by membrane contact. Juxtacrine signaling has been observed for some , cytokine and chemokine cellular signals, playing an important role in the immune response. Juxtacrine signalling via direct membrane contacts is also present between neuronal cell bodies and motile processes of microglia both during development, and in the adult brain.
Paracrine signals such as retinoic acid target only cells in the vicinity of the emitting cell. represent another example of a paracrine signal.
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 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.
Although paracrine signaling elicits a diverse array of responses in the induced cells, most paracrine factors utilize a relatively streamlined set of receptors and pathways. In fact, different organs in the body - even between different species - are known to utilize a similar sets of paracrine factors in differential development. The highly conserved receptors and pathways can be organized into four major families based on similar structures: fibroblast growth factor (FGF) family, Hedgehog family, Wnt family, and TGF-β superfamily. Binding of a paracrine factor to its respective receptor initiates signal transduction cascades, eliciting different responses.
Signaling molecules interact with a target cell as a ligand to cell surface receptors, and/or by entering into the cell through its membrane or endocytosis for intracrine signaling. This generally results in the activation of , leading to various physiological effects. 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 epithelium 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 may bind to a cell surface receptor on other yeast cells and induce them to prepare for mating.
When a presynaptic neuron is excited, it releases a neurotransmitter from vesicles into the synaptic cleft. The neurotransmitter then binds to receptors located on the postsynaptic neuron. If these receptors are ligand-gated ion channels (LICs), a resulting conformational change opens the ion channels, which leads to a flow of ions across the cell membrane. This, in turn, results in either a depolarization, for an excitatory receptor response, or a hyperpolarization, for an inhibitory response.
These receptor proteins are typically composed of at least two different domains: a transmembrane domain which includes the ion pore, and an extracellular domain which includes the ligand binding location (an allosteric binding site). This modularity has enabled a 'divide and conquer' approach to finding the structure of the proteins (crystallising each domain separately). The function of such receptors located at is to convert the chemical signal of released neurotransmitter directly and very quickly into a postsynaptic electrical signal. Many LICs are additionally modulated by allosteric ligands, by channel blockers, , or the membrane potential. LICs are classified into three superfamilies which lack evolutionary relationship: cys-loop receptors, ionotropic glutamate receptors and ATP-gated channels.
G protein-coupled receptors are found only in , including yeast, , and animals. The ligands that bind and activate these receptors include light-sensitive compounds, , , , and , and vary in size from small molecules to peptides to large . G protein-coupled receptors are involved in many diseases.
There are two principal signal transduction pathways involving the G protein-coupled receptors: cAMP signal pathway and phosphatidylinositol signal pathway. When a ligand binds to the GPCR it causes a conformational change in the GPCR, which allows it to act as a guanine nucleotide exchange factor (GEF). The GPCR can then activate an associated G protein by exchanging the GDP bound to the G protein for a GTP. The G protein's α subunit, together with the bound GTP, can then dissociate from the β and γ subunits to further affect intracellular signaling proteins or target functional proteins directly depending on the α subunit type (Gαs, Gαi/o, Gαq/11, Gα12/13).
G protein-coupled receptors are an important drug target and approximately 34% of all Food and Drug Administration (FDA) approved drugs target 108 members of this family. The global sales volume for these drugs is estimated to be 180 billion US dollars . It is estimated that GPCRs are targets for about 50% of drugs currently on the market, mainly due to their involvement in signaling pathways related to many diseases i.e. mental, metabolic including endocrinological disorders, immunological including viral infections, cardiovascular, inflammatory, senses disorders, and cancer. The long ago discovered association between GPCRs and many endogenous and exogenous substances, resulting in e.g. analgesia, is another dynamically developing field of pharmaceutical research.
They have two important domains, an extra-cellular ligand binding domain and an intracellular domain, which has a catalytic function; and a single transmembrane helix. The signaling molecule binds to the receptor on the outside of the cell and causes a conformational change on the catalytic function located on the receptor inside the cell. Examples of the enzymatic activity include:
Steroid hormone receptors are found in the cell nucleus, cytosol, and also on the plasma membrane of target cells. They are generally intracellular receptors (typically cytoplasmic or nuclear) and initiate signal transduction for which lead to changes in gene expression over a time period of hours to days. The best studied steroid hormone receptors are members of the nuclear receptor subfamily 3 (NR3) that include receptors for estrogen (group NR3A) and 3-ketosteroids (group NR3C). In addition to nuclear receptors, several G protein-coupled receptors and act as cell surface receptors for certain steroid hormones.
Receptor Phosphorylation is another type of receptor down-regulation. Biochemical changes can reduce receptor affinity for a ligand.
Reducing the sensitivity of the receptor is a result of receptors being occupied for a long time. This results in a receptor adaptation in which the receptor no longer responds to the signaling molecule. Many receptors have the ability to change in response to ligand concentration.
In some cases, receptor activation caused by ligand binding to a receptor is directly coupled to the cell's response to the ligand. For example, the neurotransmitter GABA can activate a cell surface receptor that is part of an ion channel. GABA binding to a GABAA receptor on a neuron opens a Chloride channel that is part of the receptor. GABAA receptor activation allows negatively charged chloride ions to move into the neuron, which inhibits the ability of the neuron to produce . However, for many cell surface receptors, ligand-receptor interactions are not directly linked to the cell's response. The activated receptor must first interact with other proteins inside the cell before the ultimate Physiology effect of the ligand on the cell's behavior is produced. Often, the behavior of a chain of several interacting cell proteins is altered following receptor activation. The entire set of cell changes induced by receptor activation is called a signal transduction mechanism or pathway.
A more complex signal transduction pathway is the MAPK/ERK pathway, which involves changes of protein–protein interactions inside the cell, induced by an external signal. Many growth factors bind to receptors at the cell surface and stimulate cells to progress through the cell cycle and Cell division. Several of these receptors are that start to phosphorylate themselves and other proteins when binding to a ligand. This phosphorylation can generate a binding site for a different protein and thus induce protein–protein interaction. In this case, the ligand (called epidermal growth factor, or EGF) binds to the receptor (called EGFR). This activates the receptor to phosphorylate itself. The phosphorylated receptor binds to an adaptor protein (GRB2), which couples the signal to further downstream signaling processes. For example, one of the signal transduction pathways that are activated is called the mitogen-activated protein kinase (MAPK) pathway. The signal transduction component labeled as "MAPK" in the pathway was originally called "ERK," so the pathway is called the MAPK/ERK pathway. The MAPK protein is an enzyme, a protein kinase that can attach phosphate to target proteins such as the transcription factor C-myc and, thus, alter gene transcription and, ultimately, cell cycle progression. Many cellular proteins are activated downstream of the growth factor receptors (such as EGFR) that initiate this signal transduction pathway.
Some signaling transduction pathways respond differently, depending on the amount of signaling received by the cell. For instance, the hedgehog protein activates different genes, depending on the amount of hedgehog protein present.
Complex multi-component signal transduction pathways provide opportunities for feedback, signal amplification, and interactions inside one cell between multiple signals and signaling pathways.
A specific cellular response is the result of the transduced signal in the final stage of cell signaling. This response can essentially be any cellular activity that is present in a body. It can spur the rearrangement of the cytoskeleton, or even as catalysis by an enzyme. These three steps of cell signaling all ensure that the right cells are behaving as told, at the right time, and in synchronization with other cells and their own functions within the organism. At the end, the end of a signal pathway leads to the regulation of cellular activity. This response can take place in the nucleus or in the cytoplasm of the cell. A majority of signaling pathways control protein synthesis by turning certain genes on and off in the nucleus.
In unicellular organisms such as bacteria, signaling can be used to 'activate' peers from a Dormancy, enhance virulence, defend against , etc. In quorum sensing, which is also found in social insects, the multiplicity of individual signals has the potentiality to create a positive feedback loop, generating coordinated response. In this context, the signaling molecules are called . This signaling mechanism may have been involved in evolution from unicellular to multicellular organisms. Bacteria also use contact-dependent signaling, notably to limit their growth.
Signaling molecules used by multicellular organisms are often called . They can have such purposes as alerting against danger, indicating food supply, or assisting in reproduction.
| + Brief overview of some signaling pathways (based on receptor families) that result in short-acting cellular responsesCell biology/Pollard et al,The Cell/ G.M. Cooper
!Receptor Family !Example of Ligands/ activators (Bracket: receptor for it) !Example of effectors !Further downstream effects | ||||
| Ligand Gated Ion Channels | Acetylcholine (such as Nicotinic acetylcholine receptor), | Changes in membrane permeability | Change in membrane potential | |
| Seven Helix Receptor | Light (Rhodopsin), Dopamine (Dopamine receptor), GABA (GABA receptor), Prostaglandin (prostaglandin receptor) etc. | Trimeric G protein | Adenylyl cyclase, cGMP phosphodiesterase, G-protein gated ion channel, etc. | |
| Two-component | Diverse activators | Histidine Kinase | Response Regulator - flagellar movement, Gene expression | |
| Membrane Guanylyl Cyclase | Atrial natriuretic peptide, Sea urchin egg peptide etc. | cGMP | Regulation of Kinases and channels- Diverse actions | |
| Cytoplasmic Guanylyl cyclase | Nitric Oxide (Nitric oxide receptor) | cGMP | Regulation of cGMP Gated channels, Kinases | |
| Integrins | Fibronectins, other extracellular matrix proteins | Nonreceptor tyrosine kinase | Diverse response |
| + Brief overview of some signaling pathways (based on receptor families) that control gene activity | Frizzled (special type of 7Helix receptor) | Wnt | Dishevelled, axin - APC, GSK3-beta - Beta catenin | Gene expression | |
| Two-component | Diverse activators | Histidine Kinase | Response Regulator - flagellar movement, Gene expression | ||
| Receptor Tyrosine Kinase | Insulin (insulin receptor), EGF (EGF receptor), FGF-Alpha, FGF-Beta, etc. (FGF-receptors) | Ras protein, MAP-kinases, Phospholipase C, PI3-Kinase | Gene expression change | ||
| Cytokine receptors | Erythropoietin, Growth Hormone (Growth Hormone Receptor), Interferon gamma (IFN-Gamma receptor) etc. | Janus kinase | STAT protein - Gene expression | ||
| Tyrosine kinase Linked- receptors | MHC-peptide complex - TCR, Antigens - BCR | Cytoplasmic Tyrosine Kinase | Gene expression | ||
| Receptor Serine/Threonine Kinase | Activin (activin receptor), Inhibin, Bone-morphogenetic protein (BMP Receptor), TGF-beta | Smad transcription factors | Control of gene expression | ||
| Sphingomyelinase linked receptors | IL-1 (IL-1 receptor), TNF (TNF-receptors) | Ceramide activated kinases | Gene expression | ||
| Cytoplasmic Steroid receptors | Steroid hormones, , Retinoic acid etc. | Work as/ interact with transcription factors | Gene expression |
In the case of Notch-mediated signaling, the signal transduction mechanism can be relatively simple. As shown in Figure 2, the activation of Notch can cause the Notch protein to be altered by a protease. Part of the Notch protein is released from the cell surface membrane and takes part in gene regulation. Cell signaling research involves studying the spatial and temporal dynamics of both receptors and the components of signaling pathways that are activated by receptors in various cell types. Emerging methods for single-cell mass-spectrometry analysis promise to enable studying signal transduction with single-cell resolution.
In notch signaling, direct contact between cells allows for 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 loop or system that reduces Notch expression in the cell that will differentiate and that increases Notch on the surface of the cell that continues as a stem cell.
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