Receptor antagonist

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Receptor_antagonist 

 

Antagonists will block the binding of an agonist at a receptor molecule, inhibiting the signal produced by a receptor–agonist coupling.

A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of receptor proteins. They are sometimes called blockers; examples include alpha blockers, beta blockers, and calcium channel blockers. In pharmacology, antagonists have affinity but no efficacy for their cognate receptors, and binding will disrupt the interaction and inhibit the function of an agonist or inverse agonist at receptors. Antagonists mediate their effects by binding to the active site or to the allosteric site on a receptor, or they may interact at unique binding sites not normally involved in the biological regulation of the receptor's activity. Antagonist activity may be reversible or irreversible depending on the longevity of the antagonist–receptor complex, which, in turn, depends on the nature of antagonist–receptor binding. The majority of drug antagonists achieve their potency by competing with endogenous ligands or substrates at structurally defined binding sites on receptors.

Etymology

The English word antagonist in pharmaceutical terms comes from the Greek ἀνταγωνιστής – antagonistēs, "opponent, competitor, villain, enemy, rival", which is derived from anti- ("against") and agonizesthai ("to contend for a prize"). Antagonists were discovered in the 20th century by American biologist Bailey Edgren.

Receptors

Main article: Receptor (biochemistry)

Biochemical receptors are large protein molecules that can be activated by the binding of a ligand such as a hormone or a drug. Receptors can be membrane-bound, as cell surface receptors, or inside the cell as intracellular receptors, such as nuclear receptors including those of the mitochondrion. Binding occurs as a result of non-covalent interactions between the receptor and its ligand, at locations called the binding site on the receptor. A receptor may contain one or more binding sites for different ligands. Binding to the active site on the receptor regulates receptor activation directly. The activity of receptors can also be regulated by the binding of a ligand to other sites on the receptor, as in allosteric binding sites. Antagonists mediate their effects through receptor interactions by preventing agonist-induced responses. This may be accomplished by binding to the active site or the allosteric site. In addition, antagonists may interact at unique binding sites not normally involved in the biological regulation of the receptor's activity to exert their effects.

The term antagonist was originally coined to describe different profiles of drug effects. The biochemical definition of a receptor antagonist was introduced by Ariens and Stephenson in the 1950s. The current accepted definition of receptor antagonist is based on the receptor occupancy model. It narrows the definition of antagonism to consider only those compounds with opposing activities at a single receptor. Agonists were thought to turn "on" a single cellular response by binding to the receptor, thus initiating a biochemical mechanism for change within a cell. Antagonists were thought to turn "off" that response by 'blocking' the receptor from the agonist. This definition also remains in use for physiological antagonists, substances that have opposing physiological actions, but act at different receptors. For example, histamine lowers arterial pressure through vasodilation at the histamine H₁ receptor, while adrenaline raises arterial pressure through vasoconstriction mediated by alpha-adrenergic receptor activation.

Our understanding of the mechanism of drug-induced receptor activation and receptor theory and the biochemical definition of a receptor antagonist continues to evolve. The two-state model of receptor activation has given way to multistate models with intermediate conformational states. The discovery of functional selectivity and that ligand-specific receptor conformations occur and can affect interaction of receptors with different second messenger systems may mean that drugs can be designed to activate some of the downstream functions of a receptor but not others. This means efficacy may actually depend on where that receptor is expressed, altering the view that efficacy at a receptor is receptor-independent property of a drug.

Pharmacodynamics

Main article: Pharmacodynamics

Efficacy and potency

Agonists require higher dose/concentration to achieve the same effect when in the presence of a reversible competitive antagonist.

By definition, antagonists display no efficacy to activate the receptors they bind. Antagonists do not maintain the ability to activate a receptor. Once bound, however, antagonists inhibit the function of agonists, inverse agonists, and partial agonists. In functional antagonist assays, a dose-response curve measures the effect of the ability of a range of concentrations of antagonists to reverse the activity of an agonist. The potency of an antagonist is usually defined by its half maximal inhibitory concentration (i.e., IC₅₀ value). This can be calculated for a given antagonist by determining the concentration of antagonist needed to elicit half inhibition of the maximum biological response of an agonist. Elucidating an IC₅₀ value is useful for comparing the potency of drugs with similar efficacies, however the dose-response curves produced by both drug antagonists must be similar. The lower the IC₅₀ the greater the potency of the antagonist, and the lower the concentration of drug that is required to inhibit the maximum biological response. Lower concentrations of drugs may be associated with fewer side-effects.

Agonists get its maximum effect reduced when in the presence of an Irreversible Competitive Antagonist or a Reversible Non-Competitive Antagonist.

Affinity

The affinity of an antagonist for its binding site (K_i), i.e. its ability to bind to a receptor, will determine the duration of inhibition of agonist activity. The affinity of an antagonist can be determined experimentally using Schild regression or for competitive antagonists in radioligand binding studies using the Cheng-Prusoff equation. Schild regression can be used to determine the nature of antagonism as beginning either competitive or non-competitive and K_i determination is independent of the affinity, efficacy or concentration of the agonist used. However, it is important that equilibrium has been reached. The effects of receptor desensitization on reaching equilibrium must also be taken into account. The affinity constant of antagonists exhibiting two or more effects, such as in competitive neuromuscular-blocking agents that also block ion channels as well as antagonising agonist binding, cannot be analyzed using Schild regression. Schild regression involves comparing the change in the dose ratio, the ratio of the EC₅₀ of an agonist alone compared to the EC₅₀ in the presence of a competitive antagonist as determined on a dose response curve. Altering the amount of antagonist used in the assay can alter the dose ratio. In Schild regression, a plot is made of the log (dose ratio-1) versus the log concentration of antagonist for a range of antagonist concentrations. The affinity or K_i is where the line cuts the x-axis on the regression plot. Whereas, with Schild regression, antagonist concentration is varied in experiments used to derive K_i values from the Cheng-Prusoff equation, agonist concentrations are varied. Affinity for competitive agonists and antagonists is related by the Cheng-Prusoff factor used to calculate the K_i (affinity constant for an antagonist) from the shift in IC₅₀ that occurs during competitive inhibition. The Cheng-Prusoff factor takes into account the effect of altering agonist concentration and agonist affinity for the receptor on inhibition produced by competitive antagonists.

Types

See also: Enzyme inhibitor § Types of reversible inhibitors

Competitive

Further information: Competitive inhibition

Competitive antagonists bind to receptors at the same binding site (active site) as the endogenous ligand or agonist, but without activating the receptor. Agonists and antagonists "compete" for the same binding site on the receptor. Once bound, an antagonist will block agonist binding. Sufficient concentrations of an antagonist will displace the agonist from the binding sites, resulting in a lower frequency of receptor activation. The level of activity of the receptor will be determined by the relative affinity of each molecule for the site and their relative concentrations. High concentrations of a competitive agonist will increase the proportion of receptors that the agonist occupies, higher concentrations of the antagonist will be required to obtain the same degree of binding site occupancy. In functional assays using competitive antagonists, a parallel rightward shift of agonist dose–response curves with no alteration of the maximal response is observed.

Competitive antagonists are used to prevent the activity of drugs, and to reverse the effects of drugs that have already been consumed. Naloxone (also known as Narcan) is used to reverse opioid overdose caused by drugs such as heroin or morphine. Similarly, Ro15-4513 is an antidote to alcohol and flumazenil is an antidote to benzodiazepines.

Competitive antagonists are sub-classified as reversible (surmountable) or irreversible (insurmountable) competitive antagonists, depending on how they interact with their receptor protein targets. Reversible antagonists, which bind via noncovalent intermolecular forces, will eventually dissociate from the receptor, freeing the receptor to be bound again. Irreversible antagonists bind via covalent intermolecular forces. Because there is not enough free energy to break covalent bonds in the local environment, the bond is essentially "permanent", meaning the receptor-antagonist complex will never dissociate. The receptor will thereby remain permanently antagonized until it is ubiquitinated and thus destroyed.

Non-competitive

A non-competitive antagonist is a type of insurmountable antagonist that may act in one of two ways: by binding to an allosteric site of the receptor, or by irreversibly binding to the active site of the receptor. The former meaning has been standardised by the IUPHAR, and is equivalent to the antagonist being called an allosteric antagonist. While the mechanism of antagonism is different in both of these phenomena, they are both called "non-competitive" because the end-results of each are functionally very similar. Unlike competitive antagonists, which affect the amount of agonist necessary to achieve a maximal response but do not affect the magnitude of that maximal response, non-competitive antagonists reduce the magnitude of the maximum response that can be attained by any amount of agonist. This property earns them the name "non-competitive" because their effects cannot be negated, no matter how much agonist is present. In functional assays of non-competitive antagonists, depression of the maximal response of agonist dose-response curves, and in some cases, rightward shifts, is produced. The rightward shift will occur as a result of a receptor reserve (also known as spare receptors) and inhibition of the agonist response will only occur when this reserve is depleted.

An antagonist that binds to the active site of a receptor is said to be "non-competitive" if the bond between the active site and the antagonist is irreversible or nearly so. This usage of the term "non-competitive" may not be ideal, however, since the term "irreversible competitive antagonism" may also be used to describe the same phenomenon without the potential for confusion with the second meaning of "non-competitive antagonism" discussed below.

The second form of "non-competitive antagonists" act at an allosteric site. These antagonists bind to a distinctly separate binding site from the agonist, exerting their action to that receptor via the other binding site. They do not compete with agonists for binding at the active site. The bound antagonists may prevent conformational changes in the receptor required for receptor activation after the agonist binds. Cyclothiazide has been shown to act as a reversible non-competitive antagonist of mGluR1 receptor.

Uncompetitive

Uncompetitive antagonists differ from non-competitive antagonists in that they require receptor activation by an agonist before they can bind to a separate allosteric binding site. This type of antagonism produces a kinetic profile in which "the same amount of antagonist blocks higher concentrations of agonist better than lower concentrations of agonist". Memantine, used in the treatment of Alzheimer's disease, is an uncompetitive antagonist of the NMDA receptor.

Silent antagonists

Chart demonstrating the difference between agonists, silent antagonists, and inverse agonists.

Silent antagonists are competitive receptor antagonists that have zero intrinsic activity for activating a receptor. They are true antagonists, so to speak. The term was created to distinguish fully inactive antagonists from weak partial agonists or inverse agonists.

Partial agonists

Partial agonists are defined as drugs that, at a given receptor, might differ in the amplitude of the functional response that they elicit after maximal receptor occupancy. Although they are agonists, partial agonists can act as a competitive antagonist in the presence of a full agonist, as it competes with the full agonist for receptor occupancy, thereby producing a net decrease in the receptor activation as compared to that observed with the full agonist alone. Clinically, their usefulness is derived from their ability to enhance deficient systems while simultaneously blocking excessive activity. Exposing a receptor to a high level of a partial agonist will ensure that it has a constant, weak level of activity, whether its normal agonist is present at high or low levels. In addition, it has been suggested that partial agonism prevents the adaptive regulatory mechanisms that frequently develop after repeated exposure to potent full agonists or antagonists. E.g. Buprenorphine, a partial agonist of the μ-opioid receptor, binds with weak morphine-like activity and is used clinically as an analgesic in pain management and as an alternative to methadone in the treatment of opioid dependence.

Inverse agonists

An inverse agonist can have effects similar to those of an antagonist, but causes a distinct set of downstream biological responses. Constitutively active receptors that exhibit intrinsic or basal activity can have inverse agonists, which not only block the effects of binding agonists like a classical antagonist but also inhibit the basal activity of the receptor. Many drugs previously classified as antagonists are now beginning to be reclassified as inverse agonists because of the discovery of constitutive active receptors. Antihistamines, originally classified as antagonists of histamine H₁ receptors have been reclassified as inverse agonists.

Reversibility

Many antagonists are reversible antagonists that, like most agonists, will bind and unbind a receptor at rates determined by receptor-ligand kinetics.

Irreversible antagonists covalently bind to the receptor target and, in general, cannot be removed; inactivating the receptor for the duration of the antagonist effects is determined by the rate of receptor turnover, the rate of synthesis of new receptors. Phenoxybenzamine is an example of an irreversible alpha blocker—it permanently binds to α adrenergic receptors, preventing adrenaline and noradrenaline from binding. Inactivation of receptors normally results in a depression of the maximal response of agonist dose-response curves and a right shift in the curve occurs where there is a receptor reserve similar to non-competitive antagonists. A washout step in the assay will usually distinguish between non-competitive and irreversible antagonist drugs, as effects of non-competitive antagonists are reversible and activity of agonist will be restored.

Irreversible competitive antagonists also involve competition between the agonist and antagonist of the receptor, but the rate of covalent bonding differs and depends on affinity and reactivity of the antagonist. For some antagonists, there may be a distinct period during which they behave competitively (regardless of basal efficacy), and freely associate to and dissociate from the receptor, determined by receptor-ligand kinetics. But, once irreversible bonding has taken place, the receptor is deactivated and degraded. As for non-competitive antagonists and irreversible antagonists in functional assays with irreversible competitive antagonist drugs, there may be a shift in the log concentration–effect curve to the right, but, in general, both a decrease in slope and a reduced maximum are obtained.

Cell signaling

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Cell_signaling

In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellular life in prokaryotes and eukaryotes. Signals that originate from outside a cell (or extracellular signals) can be physical agents like mechanical pressure, voltage, temperature, light, or chemical signals (e.g., small molecules, peptides, or gas). Cell signaling can occur over short or long distances, and as a result can be classified as autocrine, juxtacrine, intracrine, paracrine, or endocrine. Signaling molecules can be synthesized from various biosynthetic pathways and released through passive or active transports, or even from cell damage.

Receptors play a key role in cell signaling as they are able to detect chemical signals or physical stimuli. Receptors are generally proteins located on the cell surface or within the interior of the cell such as the cytoplasm, organelles, and nucleus. Cell surface receptors usually bind with extracellular signals (or ligands), which causes a conformational change in the receptor that leads it to initiate enzymic activity, or to open or close ion channel activity. Some receptors do not contain enzymatic or channel-like domains but are instead linked to enzymes or transporters. Other receptors like nuclear receptors have a different mechanism such as changing their DNA binding properties and cellular localization to the nucleus.

Signal transduction begins with the transformation (or transduction) of a signal into a chemical one, which can directly activate an ion channel (ligand-gated ion channel) or initiate a second messenger system cascade that propagates the signal through the cell. Second messenger systems can amplify 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 proteolytic cleavage, phosphorylation, methylation, and ubiquitinylation.

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.

Taxonomic range

In many small organisms such as bacteria, quorum sensing enables individuals to begin an activity only when the population is sufficiently large. This signaling between cells was first observed in the marine bacterium Aliivibrio fischeri, which produces light when the population is dense enough. The mechanism involves the production and detection of a signaling molecule, and the regulation of gene transcription in response. Quorum sensing operates in both gram-positive and gram-negative bacteria, and both within and between species.

In slime moulds, 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. Synaptic signaling is a special case of paracrine signaling (for chemical synapses) or juxtacrine signaling (for electrical synapses) between neurons and target cells.

Extracellular signal

Synthesis and release

Different types of extracellular signaling

Many cell signals are carried by molecules that are released by one cell and move to make contact with another cell. Signaling molecules can belong to several chemical classes: lipids, phospholipids, amino acids, monoamines, proteins, glycoproteins, or gases. Signaling molecules binding surface receptors are generally large and hydrophilic (e.g. TRH, Vasopressin, Acetylcholine), while those entering the cell are generally small and hydrophobic (e.g. glucocorticoids, thyroid hormones, cholecalciferol, retinoic acid), but important exceptions to both are numerous, and the same molecule can act both via surface receptors or in an intracrine manner to different effects. In animal cells, specialized cells release these hormones and send them through the circulatory system to other parts of the body. They then reach target cells, which can recognize and respond to the hormones and produce a result. This is also known as endocrine signaling. Plant growth regulators, or plant hormones, move through cells or by diffusing through the air as a gas to reach their targets. Hydrogen sulfide is produced in small amounts by some cells of the human body and has a number of biological signaling functions. Only two other such gases are currently known to act as signaling molecules in the human body: nitric oxide and carbon monoxide.

Exocytosis

Exocytosis is the process by which a cell transports molecules such as neurotransmitters and proteins out of the cell. As an active transport mechanism, exocytosis requires the use of energy to transport material. Exocytosis and its counterpart, endocytosis, the process that brings substances into the cell, are used by all cells because most chemical substances important to them are large polar molecules that cannot pass through the hydrophobic portion of the cell membrane by passive transport. Exocytosis is the process by which a large amount of molecules are released; thus it is a form of bulk transport. Exocytosis occurs via secretory portals at the cell plasma membrane called porosomes. Porosomes are permanent cup-shaped lipoprotein structures at the cell plasma membrane, where secretory vesicles transiently dock and fuse to release intra-vesicular contents from the cell.

In exocytosis, membrane-bound secretory vesicles are carried to the cell membrane, where they dock and fuse at porosomes and their contents (i.e., water-soluble molecules) are secreted into the extracellular environment. This secretion is possible because the vesicle transiently fuses with the plasma membrane. In the context of neurotransmission, neurotransmitters are typically released from synaptic vesicles into the synaptic cleft via exocytosis; however, neurotransmitters can also be released via reverse transport through membrane transport proteins.

Forms

Autocrine

Differences between autocrine and paracrine signaling

Autocrine signaling involves a cell secreting a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell itself. This can be contrasted with paracrine signaling, intracrine signaling, or classical endocrine signaling.

Paracrine

In paracrine signaling, a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance (local action), as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system; juxtacrine interactions; and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.

Paracrine signals such as retinoic acid target only cells in the vicinity of the emitting cell. Neurotransmitters 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 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.

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.

Endocrine

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. Endocrine signaling involves the release of hormones by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neural control center for all endocrine systems. In humans, the major endocrine glands are the thyroid gland and the adrenal glands. The study of the endocrine system and its disorders is known as endocrinology.

Juxtacrine

Juxtacrine signaling is a type of cell–cell or cell–extracellular matrix signaling in multicellular organisms that requires close contact. There are three types:

1. A membrane ligand (protein, oligosaccharide, lipid) and a membrane protein of two adjacent cells interact.
2. A communicating junction links the intracellular compartments of two adjacent cells, allowing transit of relatively small molecules.
3. An extracellular matrix glycoprotein and a membrane protein interact.

Additionally, in unicellular organisms such as bacteria, juxtacrine signaling means interactions by membrane contact. Juxtacrine signaling has been observed for some growth factors, 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.

Receptors

Main article: Receptor (biochemistry)

 

Transmembrane receptor working principle

Cells receive information from their neighbors through a class of proteins known as receptors. Receptors may bind with some molecules (ligands) or may interact with physical agents like light, mechanical temperature, pressure, etc. Reception occurs when the target cell (any cell with a receptor protein specific to the signal molecule) detects a signal, usually in the form of a small, water-soluble molecule, via binding to a receptor protein on the cell surface, or once inside the cell, the signaling molecule can bind to intracellular receptors, other elements, or stimulate enzyme activity (e.g. gasses), as in intracrine signaling.

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 second messengers, 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 epithelial and immune system cells. For the yeast Saccharomyces cerevisiae during mating, some cells send a peptide signal (mating factor pheromones) 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.

Cell surface receptors

See also: Ligand (biochemistry) and Receptor–ligand kinetics

Cell surface receptors play an essential role in the biological systems of single- and multi-cellular organisms and malfunction or damage to these proteins is associated with cancer, heart disease, and asthma. These trans-membrane receptors are able to transmit information from outside the cell to the inside because they change conformation when a specific ligand binds to it. There are three major types: Ion channel linked receptors, G protein–coupled receptors, and enzyme-linked receptors.

Ion channel linked receptors

The AMPA receptor bound to a glutamate antagonist showing the amino terminal, ligand binding, and transmembrane domain, PDB 3KG2

Ion channel linked receptors are a group of transmembrane ion-channel proteins which open to allow ions such as Na⁺, K⁺, Ca²⁺, and/or Cl⁻ to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter.

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, 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 synapses is to convert the chemical signal of presynaptically released neurotransmitter directly and very quickly into a postsynaptic electrical signal. Many LICs are additionally modulated by allosteric ligands, by channel blockers, ions, 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

A G Protein-coupled receptor within the plasma membrane.

G protein-coupled receptors are a large group of evolutionarily-related proteins that are cell surface receptors that detect molecules outside the cell and activate cellular responses. Coupling with G proteins, they are called seven-transmembrane receptors because they pass through the cell membrane seven times. Ligands can bind either to extracellular N-terminus and loops (e.g. glutamate receptors) or to the binding site within transmembrane helices (Rhodopsin-like family). They are all activated by agonists although a spontaneous auto-activation of an empty receptor can also be observed.

G protein-coupled receptors are found only in eukaryotes, including yeast, 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.

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 (G_αs, G_αi/o, G_αq/11, G_α12/13).

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 as of 2018. 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.

Enzyme-linked receptors

VEGF receptors are a type of enzyme-coupled receptors, specifically tyrosine kinase receptors

Enzyme-linked receptors (or catalytic receptors) are transmembrane receptors that, upon activation by an extracellular ligand, causes enzymatic activity on the intracellular side. Hence a catalytic receptor is an integral membrane protein possessing both enzymatic, catalytic, and receptor functions.

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:

• Receptor tyrosine kinase, as in fibroblast growth factor receptor. Most enzyme-linked receptors are of this type.
• Serine/threonine-specific protein kinase, as in bone morphogenetic protein
• Guanylate cyclase, as in atrial natriuretic factor receptor

Intracellular receptors

Main articles: Nuclear receptor and DNA-binding domain

Steroid hormone receptor

Main article: Steroid hormone receptor

Steroid hormone receptors are found in the 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 steroid hormones 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 ion channels act as cell surface receptors for certain steroid hormones.

Signal transduction pathways

Further information: Signal transduction and List of signalling pathways

When binding to the signaling molecule, the receptor protein changes in some way and starts the process of transduction, which can occur in a single step or as a series of changes in a sequence of different molecules (called a signal transduction pathway). The molecules that compose these pathways are known as relay molecules. The multistep process of the transduction stage is often composed of the activation of proteins by addition or removal of phosphate groups or even the release of other small molecules or ions that can act as messengers. The amplifying of a signal is one of the benefits to this multiple step sequence. Other benefits include more opportunities for regulation than simpler systems do and the fine-tuning of the response, in both unicellular and multicellular organism.

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 GABA_A receptor on a neuron opens a chloride-selective ion channel that is part of the receptor. GABA_A receptor activation allows negatively charged chloride ions to move into the neuron, which inhibits the ability of the neuron to produce action potentials. 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 physiological 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.

Key components of a signal transduction pathway (MAPK/ERK pathway shown)

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 divide. Several of these receptors are kinases 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 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 a 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 dormant state, enhance virulence, defend against bacteriophages, 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 autoinducers. 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 pheromones. They can have such purposes as alerting against danger, indicating food supply, or assisting in reproduction.

Short-term cellular responses

Brief overview of some signaling pathways (based on receptor families) that result in short-acting cellular responses

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	Adenylate 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

Regulating gene activity

Signal transduction pathways that lead to a cellular 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, MAP-kinases, PLC, PI3-Kinase	Gene expression change
Cytokine receptors	Erythropoietin, Growth Hormone (Growth Hormone Receptor), IFN-Gamma (IFN-Gamma receptor) etc	JAK kinase	STAT transcription factor - 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, Thyroid hormones, Retinoic acid etc	Work as/ interact with transcription factors	Gene expression

Notch signaling pathway

Notch-mediated juxtacrine signal between adjacent cells.

Notch is a cell surface protein that functions as a receptor. Animals have a small set of genes that code for signaling proteins that interact specifically with Notch receptors and stimulate a response in cells that express Notch on their surface. Molecules that activate (or, in some cases, inhibit) receptors can be classified as hormones, neurotransmitters, cytokines, and growth factors, in general called receptor ligands. Ligand receptor interactions such as that of the Notch receptor interaction, are known to be the main interactions responsible for cell signaling mechanisms and communication. notch acts as a receptor for ligands that are expressed on adjacent cells. While some receptors are cell-surface proteins, others are found inside cells. For example, estrogen is a hydrophobic molecule that can pass through the lipid bilayer of the membranes. As part of the endocrine system, intracellular estrogen receptors from a variety of cell types can be activated by estrogen produced in the ovaries.

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.