NO 2 converts to the colorless dinitrogen tetroxide (N 2O 4) at low temperatures and reverts to NO 2 at higher temperatures.
Nitrogen dioxide is a chemical compound with the formula NO2. One of several nitrogen oxides, nitrogen dioxide is a reddish-brown gas. It is a paramagnetic, bent molecule with C2vpoint group symmetry. Industrially, NO2 is an intermediate in the synthesis of nitric acid, millions of tons of which are produced each year, primarily for the production of fertilizers.
Nitrogen dioxide is poisonous and can be fatal if inhaled in large quantities. Cooking with a gas stove produces nitrogen dioxide which causes poorer indoor air quality. Combustion of gas can lead to increased concentrations of nitrogen dioxide throughout the home environment which is linked to respiratory issues and diseases. The LC50 (median lethal dose) for humans has been estimated to be 174 ppm for a 1-hour exposure. It is also included in the NOx family of atmospheric pollutants.
Properties
Nitrogen
dioxide is a reddish-brown gas with a pungent, acrid odor above 21.2 °C
(70.2 °F; 294.3 K) and becomes a yellowish-brown liquid below 21.2 °C
(70.2 °F; 294.3 K). It forms an equilibrium with its dimer, dinitrogen tetroxide (N2O4), and converts almost entirely to N2O4 below −11.2 °C (11.8 °F; 261.9 K).
The bond length between the nitrogen atom and the oxygen atom is 119.7 pm. This bond length is consistent with a bond order between one and two.
Unlike ozone (O3) the groundelectronic state of nitrogen dioxide is a doublet state, since nitrogen has one unpaired electron, which decreases the alpha effect compared with nitrite and creates a weak bonding interaction with the oxygen lone pairs. The lone electron in NO2 also means that this compound is a free radical, so the formula for nitrogen dioxide is often written as •NO2.
The reddish-brown color is a consequence of preferential
absorption of light in the blue region of the spectrum (400–500 nm),
although the absorption extends throughout the visible (at shorter
wavelengths) and into the infrared (at longer wavelengths). Absorption
of light at wavelengths shorter than about 400 nm results in photolysis
(to form NO + O, atomic oxygen); in the atmosphere the addition of the oxygen atom so formed to O2 results in ozone.
Industrially, nitrogen dioxide is produced and transported as its cryogenic liquid dimer, dinitrogen tetroxide. It is produced industrially by the oxidation of ammonia, the Ostwald Process. This reaction is the first step in the production of nitric acid:
Instead, most laboratory syntheses stabilize and then heat the nitric
acid to accelerate the decomposition. For example, the thermal
decomposition of some metal nitrates generates NO2:
NO2 is generated by the reduction of concentrated nitric acid with a metal (such as copper):
4 HNO3 + Cu → Cu(NO3)2 + 2 NO2 + 2 H2O
Selected reactions
Nitric acid decomposes slowly to nitrogen dioxide by the overall reaction:
4 HNO3 → 4 NO2 + 2 H2O + O2
The nitrogen dioxide so formed confers the characteristic yellow
color often exhibited by this acid. However, the reaction is too slow
to be a practical source of NO2.
Thermal properties
At low temperatures, NO2 reversibly converts to the colourless gas dinitrogen tetroxide (N2O4):
2 NO2 ⇌ N2O4
The exothermic equilibrium has enthalpy changeΔH = −57.23 kJ/mol.
At 150 °C (302 °F; 423 K), NO2 decomposes with release of oxygen via an endothermic process (ΔH = 14 kJ/mol):
2 NO2 →2 NO + O2
As an oxidizer
As suggested by the weakness of the N–O bond, NO2 is a good oxidizer. Consequently, it will combust, sometimes explosively, in the presence of hydrocarbons.
This reaction is one of the steps in the Ostwald process for the industrial production of nitric acid from ammonia. This reaction is negligibly slow at low concentrations of NO2 characteristic of the ambient atmosphere, although it does proceed upon NO2 uptake to surfaces. Such surface reaction is thought to produce gaseous HNO2 (often written as HONO) in outdoor and indoor environments.
Conversion to nitrates
NO2 is used to generate anhydrous metal nitrates from the oxides:
MO + 3 NO2 → M(NO3)2 + NO
Alkyl and metal iodides give the corresponding nitrates:
TiI4 + 8 NO2 → Ti(NO3)4 + 4 NO + 2 I2
With organic compounds
The reactivity of nitrogen dioxide toward organic compounds has long been known. For example, it reacts with amides to give N-nitroso derivatives. It is used for nitrations under anhydrous conditions.
Nitrogen dioxide tropospheric column density in 2011.
Nitrogen dioxide typically arises via the oxidation of nitric oxide by oxygen in air (e.g. as result of corona discharge):
2 NO + O2 → 2 NO2
NO2 is introduced into the environment by natural causes, including entry from the stratosphere, bacterial respiration, volcanos, and lightning. These sources make NO2 a trace gas in the atmosphere of Earth, where it plays a role in absorbing sunlight and regulating the chemistry of the troposphere, especially in determining ozone concentrations.
Nitrogen dioxide also forms in most combustion processes. At elevated temperatures nitrogen combines with oxygen to form nitrogen dioxide:
N2 + 2 O2 → 2 NO2
For the general public, the most prominent sources of NO2 are internal combustion engines, as combustion temperatures are high enough to thermally combine some of the nitrogen and oxygen in the air to form NO2. Nitrogen dioxide accounts for a small fraction (generally well under 0.1) of NOx auto emissions.
Outdoors, NO2 can be a result of traffic from motor vehicles. Indoors, exposure arises from cigarette smoke, and butane and kerosene heaters and stoves. Indoor exposure levels of NO2 are, on average, at least three times higher in homes with gas stoves compared to electric stoves.
Workers in industries where NO2 is used are also exposed and are at risk for occupational lung diseases, and NIOSH has set exposure limits and safety standards. Workers in high voltage areas especially those with spark or plasma creation are at risk. Agricultural workers can be exposed to NO2 arising from grain decomposing in silos; chronic exposure can lead to lung damage in a condition called "silo-filler's disease".
Toxicity
Possible pathways implicated in long-term nitrogen dioxide exposure. Dotted lines indicate findings only supported by animal studies, while solid lines indicate findings from controlled human exposure studies. Dashed lines indicate speculative links to asthma exacerbation and respiratory tract infections. ELF = epithelial lining fluid.
NO2 diffuses into the epithelial lining fluid (ELF) of the respiratory epithelium and dissolves. There, it chemically reacts with antioxidant and lipid molecules in the ELF. The health effects of NO2 are caused by the reaction products or their metabolites, which are reactive nitrogen species and reactive oxygen species that can drive bronchoconstriction, inflammation, reduced immune response, and may have effects on the heart.
Acute exposure
Acute harm due to NO2 exposure is rare. 100–200 ppm can cause mild irritation of the nose and throat, 250–500 ppm can cause edema, leading to bronchitis or pneumonia,
and levels above 1000 ppm can cause death due to asphyxiation from
fluid in the lungs. There are often no symptoms at the time of exposure
other than transient cough, fatigue or nausea, but over hours
inflammation in the lungs causes edema.
For skin or eye exposure, the affected area is flushed with saline. For inhalation, oxygen is administered, bronchodilators may be administered, and if there are signs of methemoglobinemia, a condition that arises when nitrogen-based compounds affect the hemoglobin in red blood cells, methylene blue may be administered.
Exposure to low levels of NO2 over time can cause changes in lung function. Cooking with a gas stove is associated with poorer indoor air quality. Combustion of gas can lead to increased concentrations of nitrogen dioxide throughout the home environment which is linked to respiratory issues and diseases. Children exposed to NO2 are more likely to be admitted to hospital with asthma.
In 2019, the Court of Justice of the EU, found that France did not comply with the limit values of the EU air quality standards applicable to the concentrations of nitrogen dioxide (NO2) in 12 air quality zones.
Environmental effects
Interaction of NO2 and other NOx with water, oxygen and other chemicals in the atmosphere can form acid rain which harms sensitive ecosystems such as lakes and forests. Elevated levels of NO 2 can also harm vegetation, decreasing growth, and reduce crop yields.
Typically, the signaling process involves three components: the signal, the receptor, and the effector.
In biology, signals are mostly chemical in nature, but can also be physical cues such as pressure, voltage, temperature, or light. Chemical signals are molecules with the ability to bind and activate a specific receptor. These molecules, also referred to as ligands, are chemically diverse, including ions (e.g. Na+, K+, Ca2+,
etc.), lipids (e.g. steroid, prostaglandin), peptides (e.g. insulin,
ACTH), carbohydrates, glycosylated proteins (proteoglycans), nucleic
acids, etc. Peptide and lipid ligands are particularly important, as
most hormones belong to these classes of chemicals. Peptides are usually
polar, hydrophilic molecules. As such they are unable to diffuse freely
across the bi-lipid layer of the plasma membrane, so their action is
mediated by a cell membrane bound receptor. On the other hand,
liposoluble chemicals such as steroid hormones, can diffuse passively
across the plasma membrane and interact with intracellular receptors.
Cell signaling can occur over short or long distances, and can be
further classified as autocrine, intracrine, juxtacrine, paracrine, or endocrine. Autocrine signaling occurs when the chemical signal acts on the same cell that produced the signaling chemical. Intracrine signaling occurs when the chemical signal produced by a cell
acts on receptors located in the cytoplasm or nucleus of the same cell. Juxtacrine signaling occurs between physically adjacent cells. Paracrine signaling occurs between nearby cells. Endocrine interaction
occurs between distant cells, with the chemical signal usually carried
by the blood.
Receptors
are complex proteins or tightly bound multimer of proteins, located in
the plasma membrane or within the interior of the cell such as in the cytoplasm, organelles, and nucleus.
Receptors have the ability to detect a signal either by binding to a
specific chemical or by undergoing a conformational change when
interacting with physical agents. It is the specificity of the chemical
interaction between a given ligand and its receptor that confers the
ability to trigger a specific cellular response. Receptors can be
broadly classified into cell membrane receptors and intracellular
receptors.
Diagram of G-protein coupled reception
Cell membrane receptors can be further classified into ion channel linked receptors, G-Protein coupled receptors and enzyme linked receptors.
Ion channels receptors are large transmembrane proteins with a
ligand activated gate function. When these receptors are activated, they
may allow or block passage of specific ions across the cell membrane.
Most receptors activated by physical stimuli such as pressure or
temperature belongs to this category.
G-protein receptors
are multimeric proteins embedded within the plasma membrane. These
receptors have extracellular, trans-membrane and intracellular domains.
The extracellular domain is responsible for the interaction with a
specific ligand. The intracellular domain is responsible for the
initiation of a cascade of chemical reactions which ultimately triggers
the specific cellular function controlled by the receptor.
Enzyme-linked receptors
are transmembrane proteins with an extracellular domain responsible for
binding a specific ligand and an intracellular domain with enzymatic or
catalytic activity. Upon activation the enzymatic portion is
responsible for promoting specific intracellular chemical reactions.
Intracellular receptors have a different mechanism of action.
They usually bind to lipid soluble ligands that diffuse passively
through the plasma membrane such as steroid hormones. These ligands bind
to specific cytoplasmic transporters that shuttle the
hormone-transporter complex inside the nucleus where specific genes are
activated and the synthesis of specific proteins is promoted.
The effector component of the signaling pathway begins with signal transduction.
In this process, the signal, by interacting with the receptor, starts a
series of molecular events within the cell leading to the final effect
of the signaling process. Typically the final effect consists in the
activation of an ion channel (ligand-gated ion channel) or the initiation of a second messenger system
cascade that propagates the signal through the cell. Second messenger
systems can amplify or modulate a signal, in which activation of a few
receptors results in multiple secondary messengers being activated,
thereby amplifying the initial signal (the first messenger). The downstream effects of these signaling pathways may include additional enzymatic activities such as proteolytic cleavage, phosphorylation, methylation, and ubiquitinylation.
Signaling molecules can be synthesized from various biosynthetic pathways and released through passive or active transports, or even from cell damage.
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 molds,
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.
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.
Intracrine
In intracrine signaling,
the signaling chemicals are produced inside the cell and bind to
cytosolic or nuclear receptors without being secreted from the cell. The
intracrine signals not being secreted outside of the cell is what sets
apart intracrine signaling from the other cell signaling mechanisms such
as autocrine signaling. In both autocrine and intracrine signaling, the
signal has an effect on the cell that produced it.
A communicating junction links the intracellular compartments of two adjacent cells, allowing transit of relatively small molecules.
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.
Paracrine
This
image depicts paracrine signaling, where a secretory cell releases
signaling molecules that diffuse and trigger cellular responses in
nearby target cells
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
This
image displays endocrine signaling, the process by which endocrine
glands produce hormones that are released into the bloodstream, allowing
them to travel to distant target cells and bind to specific receptors,
triggering a cellular response.
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.
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 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 transmembraneion-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
(LICs), a resulting conformational change opens the ion channels, which
leads to a flow of ions across the cell membrane. This, in turn,
results in either a depolarization, for an excitatory receptor response, or a hyperpolarization, for an inhibitory response.
These receptor proteins are typically composed of at least two
different domains: a transmembrane domain which includes the ion pore,
and an extracellular domain which includes the ligand binding location
(an allosteric
binding site). This modularity has enabled a 'divide and conquer'
approach to finding the structure of the proteins (crystallising each
domain separately). The function of such receptors located at 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. The G-protein acts as a "middle man" transferring the
signal from its activated receptor to its target and therefore
indirectly regulates that target protein. 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 (Gαs, Gαi/o, Gαq/11, Gα12/13).
G protein-coupled receptors are an important drug target and approximately 34% of all Food and Drug Administration (FDA) approved drugs target 108
members of this family. The global sales volume for these drugs is
estimated to be 180 billion US dollars 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
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:
Intracellular receptors exist freely in the cytoplasm, nucleus, or can be bound to organelles or membranes. For example, the presence of nuclear and mitochondrial receptors is well documented. The binding of a ligand to the intracellular receptor typically induces
a response in the cell. Intracellular receptors often have a level of
specificity, this allows the receptors to initiate certain responses
when bound to a corresponding ligand. Intracellular receptors typically act on lipid soluble molecules. The receptors bind to a group of DNA binding proteins. Upon binding, the receptor-ligand complex translocates to the nucleus where they can alter patterns of gene expression.
Receptor mediated endocytosis is common way of turning receptors "off". Endocytic down regulation is regarded as a means for reducing receptor signaling. The process involves the binding of a ligand to the receptor, which
then triggers the formation of coated pits, the coated pits transform to
coated vesicles and are transported to the endosome.
Receptor Phosphorylation is another type of receptor
down-regulation. Biochemical changes can reduce receptor affinity for a
ligand.
Reducing the sensitivity of the receptor is a result of receptors
being occupied for a long time. This results in a receptor adaptation
in which the receptor no longer responds to the signaling molecule. Many
receptors have the ability to change in response to ligand
concentration.
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 GABAA receptor on a neuron opens a chloride-selective ion channel that is part of the receptor. GABAA
receptor activation allows negatively charged chloride ions to move
into the neuron, which inhibits the ability of the neuron to produce 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 factorMYC
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)
Signal transduction pathways that lead to a cellular response
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.
