Black body

From Wikipedia, the free encyclopedia

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

A black body radiator used in CARLO laboratory in Poland. It is an approximation of a model described by Planck's law utilized as a spectral irradiance standard.

 

As the temperature of a black body decreases, its intensity also decreases and its peak moves to longer wavelengths. Shown for comparison is the classical Rayleigh–Jeans law and its ultraviolet catastrophe.

A black body or blackbody is an idealized physical body that absorbs all incident electromagnetic radiation, regardless of frequency or angle of incidence. The radiation emitted by a black body in thermal equilibrium with its environment is called black-body radiation. The name "black body" is given because it absorbs all colors of light. In contrast, a white body is one with a "rough surface that reflects all incident rays completely and uniformly in all directions."

A black body in thermal equilibrium (that is, at a constant temperature) emits electromagnetic black-body radiation. The radiation is emitted according to Planck's law, meaning that it has a spectrum that is determined by the temperature alone (see figure at right), not by the body's shape or composition.

An ideal black body in thermal equilibrium has two main properties:

1. It is an ideal emitter: at every frequency, it emits as much or more thermal radiative energy as any other body at the same temperature.
2. It is a diffuse emitter: measured per unit area perpendicular to the direction, the energy is radiated isotropically, independent of direction.

Real materials emit energy at a fraction—called the emissivity—of black-body energy levels. By definition, a black body in thermal equilibrium has an emissivity ε = 1. A source with a lower emissivity, independent of frequency, is often referred to as a gray body. Constructing black bodies with an emissivity as close to 1 as possible remains a topic of current interest.

In astronomy, the radiation from stars and planets is sometimes characterized in terms of an effective temperature, the temperature of a black body that would emit the same total flux of electromagnetic energy.

Definition

The idea of a black body originally was introduced by Gustav Kirchhoff in 1860 as follows:

...the supposition that bodies can be imagined which, for infinitely small thicknesses, completely absorb all incident rays, and neither reflect nor transmit any. I shall call such bodies perfectly black, or, more briefly, black bodies.

A more modern definition drops the reference to "infinitely small thicknesses":

An ideal body is now defined, called a blackbody. A blackbody allows all incident radiation to pass into it (no reflected energy) and internally absorbs all the incident radiation (no energy transmitted through the body). This is true for radiation of all wavelengths and for all angles of incidence. Hence the blackbody is a perfect absorber for all incident radiation.

Idealizations

This section describes some concepts developed in connection with black bodies.

An approximate realization of a black body as a tiny hole in an insulated enclosure

Cavity with a hole

A widely used model of a black surface is a small hole in a cavity with walls that are opaque to radiation. Radiation incident on the hole will pass into the cavity, and is very unlikely to be re-emitted if the cavity is large. The hole is not quite a perfect black surface—in particular, if the wavelength of the incident radiation is greater than the diameter of the hole, part will be reflected. Similarly, even in perfect thermal equilibrium, the radiation inside a finite-sized cavity will not have an ideal Planck spectrum for wavelengths comparable to or larger than the size of the cavity.

Suppose the cavity is held at a fixed temperature T and the radiation trapped inside the enclosure is at thermal equilibrium with the enclosure. The hole in the enclosure will allow some radiation to escape. If the hole is small, radiation passing in and out of the hole has negligible effect upon the equilibrium of the radiation inside the cavity. This escaping radiation will approximate black-body radiation that exhibits a distribution in energy characteristic of the temperature T and does not depend upon the properties of the cavity or the hole, at least for wavelengths smaller than the size of the hole. See the figure in the Introduction for the spectrum as a function of the frequency of the radiation, which is related to the energy of the radiation by the equation E = hf, with E = energy, h = Planck's constant, f = frequency.

At any given time the radiation in the cavity may not be in thermal equilibrium, but the second law of thermodynamics states that if left undisturbed it will eventually reach equilibrium, although the time it takes to do so may be very long. Typically, equilibrium is reached by continual absorption and emission of radiation by material in the cavity or its walls. Radiation entering the cavity will be "thermalized" by this mechanism: the energy will be redistributed until the ensemble of photons achieves a Planck distribution. The time taken for thermalization is much faster with condensed matter present than with rarefied matter such as a dilute gas. At temperatures below billions of Kelvin, direct photon–photon interactions are usually negligible compared to interactions with matter. Photons are an example of an interacting boson gas, and as described by the H-theorem, under very general conditions any interacting boson gas will approach thermal equilibrium.

Transmission, absorption, and reflection

A body's behavior with regard to thermal radiation is characterized by its transmission τ, absorption α, and reflection ρ.

The boundary of a body forms an interface with its surroundings, and this interface may be rough or smooth. A nonreflecting interface separating regions with different refractive indices must be rough, because the laws of reflection and refraction governed by the Fresnel equations for a smooth interface require a reflected ray when the refractive indices of the material and its surroundings differ. A few idealized types of behavior are given particular names:

An opaque body is one that transmits none of the radiation that reaches it, although some may be reflected. That is, τ = 0 and α + ρ = 1.

A transparent body is one that transmits all the radiation that reaches it. That is, τ = 1 and α = ρ = 0.

A grey body is one where α, ρ and τ are constant for all wavelengths; this term also is used to mean a body for which α is temperature- and wavelength-independent.

A white body is one for which all incident radiation is reflected uniformly in all directions: τ = 0, α = 0, and ρ = 1.

For a black body, τ = 0, α = 1, and ρ = 0. Planck offers a theoretical model for perfectly black bodies, which he noted do not exist in nature: besides their opaque interior, they have interfaces that are perfectly transmitting and non-reflective.

Kirchhoff's perfect black bodies

Kirchhoff in 1860 introduced the theoretical concept of a perfect black body with a completely absorbing surface layer of infinitely small thickness, but Planck noted some severe restrictions upon this idea. Planck noted three requirements upon a black body: the body must (i) allow radiation to enter but not reflect; (ii) possess a minimum thickness adequate to absorb the incident radiation and prevent its re-emission; (iii) satisfy severe limitations upon scattering to prevent radiation from entering and bouncing back out. As a consequence, Kirchhoff's perfect black bodies that absorb all the radiation that falls on them cannot be realized in an infinitely thin surface layer, and impose conditions upon scattering of the light within the black body that are difficult to satisfy.

Realizations

A realization of a black body refers to a real world, physical embodiment. Here are a few.

Cavity with a hole

In 1898, Otto Lummer and Ferdinand Kurlbaum published an account of their cavity radiation source. Their design has been used largely unchanged for radiation measurements to the present day. It was a hole in the wall of a platinum box, divided by diaphragms, with its interior blackened with iron oxide. It was an important ingredient for the progressively improved measurements that led to the discovery of Planck's law. A version described in 1901 had its interior blackened with a mixture of chromium, nickel, and cobalt oxides. See also Hohlraum.

Near-black materials

There is interest in blackbody-like materials for camouflage and radar-absorbent materials for radar invisibility. They also have application as solar energy collectors, and infrared thermal detectors. As a perfect emitter of radiation, a hot material with black body behavior would create an efficient infrared heater, particularly in space or in a vacuum where convective heating is unavailable. They are also useful in telescopes and cameras as anti-reflection surfaces to reduce stray light, and to gather information about objects in high-contrast areas (for example, observation of planets in orbit around their stars), where blackbody-like materials absorb light that comes from the wrong sources.

It has long been known that a lamp-black coating will make a body nearly black. An improvement on lamp-black is found in manufactured carbon nanotubes. Nano-porous materials can achieve refractive indices nearly that of vacuum, in one case obtaining average reflectance of 0.045%. In 2009, a team of Japanese scientists created a material called nanoblack which is close to an ideal black body, based on vertically aligned single-walled carbon nanotubes. This absorbs between 98% and 99% of the incoming light in the spectral range from the ultra-violet to the far-infrared regions.

Other examples of nearly perfect black materials are super black, prepared by chemically etching a nickel–phosphorus alloy, vertically aligned carbon nanotube arrays (like VantaBlack) and flower carbon nanostructures; all absorb 99.9% of light or more.

Stars and planets

For more about the UBV color index, see Photometric system.

 

An idealized view of the cross-section of a star. The photosphere contains photons of light nearly in thermal equilibrium, and some escape into space as near-black-body radiation.

A star or planet often is modeled as a black body, and electromagnetic radiation emitted from these bodies as black-body radiation. The figure shows a highly schematic cross-section to illustrate the idea. The photosphere of the star, where the emitted light is generated, is idealized as a layer within which the photons of light interact with the material in the photosphere and achieve a common temperature T that is maintained over a long period of time. Some photons escape and are emitted into space, but the energy they carry away is replaced by energy from within the star, so that the temperature of the photosphere is nearly steady. Changes in the core lead to changes in the supply of energy to the photosphere, but such changes are slow on the time scale of interest here. Assuming these circumstances can be realized, the outer layer of the star is somewhat analogous to the example of an enclosure with a small hole in it, with the hole replaced by the limited transmission into space at the outside of the photosphere. With all these assumptions in place, the star emits black-body radiation at the temperature of the photosphere.

Effective temperature of a black body compared with the B-V and U-B color index of main sequence and super giant stars in what is called a color-color diagram.

Using this model the effective temperature of stars is estimated, defined as the temperature of a black body that yields the same surface flux of energy as the star. If a star were a black body, the same effective temperature would result from any region of the spectrum. For example, comparisons in the B (blue) or V (visible) range lead to the so-called B-V color index, which increases the redder the star, with the Sun having an index of +0.648 ± 0.006. Combining the U (ultraviolet) and the B indices leads to the U-B index, which becomes more negative the hotter the star and the more the UV radiation. Assuming the Sun is a type G2 V star, its U-B index is +0.12. The two indices for two types of most common star sequences are compared in the figure (diagram) with the effective surface temperature of the stars if they were perfect black bodies. There is a rough correlation. For example, for a given B-V index measurement, the curves of both most common sequences of star (the main sequence and the supergiants) lie below the corresponding black-body U-B index that includes the ultraviolet spectrum, showing that both groupings of star emit less ultraviolet light than a black body with the same B-V index. It is perhaps surprising that they fit a black body curve as well as they do, considering that stars have greatly different temperatures at different depths. For example, the Sun has an effective temperature of 5780 K, which can be compared to the temperature of its photosphere (the region generating the light), which ranges from about 5000 K at its outer boundary with the chromosphere to about 9500 K at its inner boundary with the convection zone approximately 500 km (310 mi) deep.

Black holes

See also: Hawking radiation

A black hole is a region of spacetime from which nothing escapes. Around a black hole there is a mathematically defined surface called an event horizon that marks the point of no return. It is called "black" because it absorbs all the light that hits the horizon, reflecting nothing, making it almost an ideal black body (radiation with a wavelength equal to or larger than the diameter of the hole may not be absorbed, so black holes are not perfect black bodies). Physicists believe that to an outside observer, black holes have a non-zero temperature and emit black-body radiation, radiation with a nearly perfect black-body spectrum, ultimately evaporating. The mechanism for this emission is related to vacuum fluctuations in which a virtual pair of particles is separated by the gravity of the hole, one member being sucked into the hole, and the other being emitted. The energy distribution of emission is described by Planck's law with a temperature T:

${\displaystyle T=\frac{\hslash c^3}{8\pi G{k}_{\text{B}}M},}$

where c is the speed of light, ℏ is the reduced Planck constant, k_B is the Boltzmann constant, G is the gravitational constant and M is the mass of the black hole. These predictions have not yet been tested either observationally or experimentally.

Cosmic microwave background radiation

See also: Big Bang and Cosmic microwave background radiation

The Big Bang theory is based upon the cosmological principle, which states that on large scales the Universe is homogeneous and isotropic. According to theory, the Universe approximately a second after its formation was a near-ideal black body in thermal equilibrium at a temperature above 10¹⁰ K. The temperature decreased as the Universe expanded and the matter and radiation in it cooled. The cosmic microwave background radiation observed today is "the most perfect black body ever measured in nature". It has a nearly ideal Planck spectrum at a temperature of about 2.7 K. It departs from the perfect isotropy of true black-body radiation by an observed anisotropy that varies with angle on the sky only to about one part in 100,000.

Radiative cooling

Log-log graphs of peak emission wavelength and radiant exitance vs black-body temperature – red arrows show that 5780 K black bodies have 501 nm peak wavelength and 63.3 MW/m²; radiant exitance

 

See also: Radiative cooling and Radiosity (heat transfer)

The integration of Planck's law over all frequencies provides the total energy per unit of time per unit of surface area radiated by a black body maintained at a temperature T, and is known as the Stefan–Boltzmann law:

${\displaystyle P/A=\sigma T^4,}$

where σ is the Stefan–Boltzmann constant, σ ≈ 5.67×10⁻⁸ W⋅m⁻²⋅K⁻⁴ To remain in thermal equilibrium at constant temperature T, the black body must absorb or internally generate this amount of power P over the given area A.

The cooling of a body due to thermal radiation is often approximated using the Stefan–Boltzmann law supplemented with a "gray body" emissivity ε ≤ 1 (P/A = εσT⁴). The rate of decrease of the temperature of the emitting body can be estimated from the power radiated and the body's heat capacity. This approach is a simplification that ignores details of the mechanisms behind heat redistribution (which may include changing composition, phase transitions or restructuring of the body) that occur within the body while it cools, and assumes that at each moment in time the body is characterized by a single temperature. It also ignores other possible complications, such as changes in the emissivity with temperature, and the role of other accompanying forms of energy emission, for example, emission of particles like neutrinos.

If a hot emitting body is assumed to follow the Stefan–Boltzmann law and its power emission P and temperature T are known, this law can be used to estimate the dimensions of the emitting object, because the total emitted power is proportional to the area of the emitting surface. In this way it was found that X-ray bursts observed by astronomers originated in neutron stars with a radius of about 10 km, rather than black holes as originally conjectured. An accurate estimate of size requires some knowledge of the emissivity, particularly its spectral and angular dependence.

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.