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# Signal transduction

Physiology

#### Description

In biology, signal transduction is any process by which a cell converts one kind of signal or stimulus into another. Processes referred to as signal transduction often involve a sequence of biochemical reactions inside the cell, which are carried out by enzymes and linked through second messengers. Such processes take place in as little time as a millisecond or as long as a few seconds. Slower processes are rarely referred to as signal transduction.

In many transduction processes, an increasing number of enzymes and other molecules become engaged in the events that proceed from the initial stimulus. In such cases the chain of steps is referred to as a "signaling cascade" or a "second messenger pathway" and often results in a small stimulus eliciting a large response.

In bacteria and other one-cell organisms, the variety of signal transduction processes of which the cell is capable influences how many ways it can react and respond to its environment. In a less direct way the same is true of animals and plants. Sensing in all forms of life depends, at the cellular level, on signal transduction.

#### Stimuli

The environment of a cell may impinge on it in many ways: different kinds of molecules may buffet its surface, its body may be heated or cooled, it may be struck by light of various wavelengths, stretched, sheared or electrified (the nerves and muscles, for example). Signal transduction mediates how cells respond to such stimuli.

Most stimuli impinge from the outside and interact with the cell membrane. Several "signaling molecules", such as the neurotransmitters, allow nerve cells to communicate across synapses, bind to receptor proteins in the membrane and open their ion channels.

#### Responses

Include activation of a gene, the production of metabolic energy and cell locomotion, for example through remodelling of the cell skeleton.

Gene activation leads to further effects, since genes are expressed as proteins, many of which are enzymes, transcription factors or other regulators of metabolic activity. Because transcription factors can activate still more genes in turn, an initial stimulus can trigger via signal transduction the expression of entire suite of genes and a panopoly of physiological events. Such mass activations are often referred to as "genetic programs," one example being the sequence of events that take place when an egg is fertilized by a sperm.

#### Types of signals

##### Extracellular

Signal transduction usually involves the binding of extracellular signaling molecules to receptors that face outwards from the membrane and trigger events inside. This takes place via a change in the shape or conformation of the receptor which occurs when the signal molecule "docks" or binds. Receptors typically respond only to the specific molecule or ligand for which they have affinity, and molecules that are even only slightly different tend to have no effect or else to act as inhibitors.

Most extracellular chemical signals are hydrophilic and are unable to penetrate the lipid membrane that surrounds cells. A common kind of extracellular signal is nutrient. In complex organisms this includes the ligands responsible for sensations of smell and taste. Steroids represent an example of extracellular signals that can cross the membrane to permeate cells, which they are able to do because they are lipophilic (see also hydrophobic).

##### Intracellular

Often, but not always, the intracellular events triggered by the external signal are considered distinct from the event of "transduction" itself, which in the strictest sense refers only to the step that converts the extracellular signal to an intracellular one.

Intracellular signalling molecules in eukaryotic cells include heterotrimeric G protein, small GTPases, cyclic nucleotides, such as cyclic AMP (cAMP) and cyclic GMP (cGMP), calcium ion, phophoinositide derivatives, such as Phosphatidylinositol-triphosphate (PIP3), Diacylglycerol (DAG) and Inositol-triphosphate (IP3), and various protein kinases and phosphatases. Some of these are also called second messengers.

##### Intercellular

Intercellular communication is accomplished by extracellular signalling and takes place in multicellular organisms. Within endocrinology, which is the study of intercellular signalling in animals, intercellular signalling is subdivided into the following types:

• Endocrine signals are produced by endocrine cells and travel through the blood to reach all parts of the body.
• Paracrine signals target only cells in the vicinity of the emitting cell. Neurotransmitters represent an example.
• Autocrine signals affect only cells that are of the same cell type as the emitting cell. An example for autocrine signals is found in immune cells.
• Juxtacrine signals are transmitted along cell membranes via protein or lipid components integral to the membrane and are capable of affecting either the emitting cell or cells immediately adjacent.

#### Types of receptors

##### Transmembrane receptors

Transmembrane receptors are proteins that span the thickness of the plasma membrane of the cell, with one end of the receptor outside (extracellular domain) and one inside (intracellular domain) the cell. When the extracellular domain recognizes the hormone, the whole receptor undergoes a structural shift that affects the intracellular domain, leading to further action. In this case the hormone itself does not pass through the plasma membrane into the cell.

##### Hormone recognition by transmembrane receptors

The binding of the hormone by the hormone receptor uses the same non-covalent mechanisms, such as hydrogen bonds, electrostatic forces, hydrophobic and Van der Waals forces. The binding affinity of a hormone to its cognate hormone receptor is expressed as a Kd:

K_d = { { [H] * [R] } \over { [HR] } }

[R] is concentration of receptor, [H] is concentration of free hormone, [HR] is concentration of receptor-bound hormone.

The important value for the strength of the signal relayed by the receptor is the concentration of the hormone-receptor complex, which is defined by the affinity of the hormone for the receptor, the concentration of the hormone and, of course, the concentration of the receptor. The concentration of the circulating hormone is the key value for the strength of the signal, since the other two values are constant. For fast reaction, the hormone-producing cells can store prehormones, and quickly modify and release them if necessary. Also, the recipient cell can modify the sensitivity of the receptor, for example by phosphorylation; also, the variation of the number of receptors can vary the total signal strength in the recipient cell.

##### Signal transduction of transmembrane receptors by structural changes

Signal transduction across the plasma membrane is possible only by many components working together. First, the receptor has to recognize the hormone with the extracellular domain, then activate other proteins within the cytosol with its cytoplasmic domain, which the protein does through a shift in conformation. The activated effector proteins usually stay close to the membrane, or are anchored within the membrane by lipid anchors, a posttranslational modification (see myristoilation, palmitorylation, farnesylation, geranylation, and the glycosyl-phosphatidyl-inositol-anchor). Many membrane-associated proteins can be activated in turn, or come together to form a multi-protein complex that finally sends a signal via a soluble molecule into the cell.

##### Signal transduction of transmembrane receptors that are ion channels

A ligand-activated ion channel will recognize its ligand, and then undergo a structural change that opens a gap (channel) in the plasma membrane through which ions can pass. These ions will then relay the signal. An example for this mechanism is found in the receiving cell of a synapse.

##### Signal transduction of transmembrane receptors on change of transmembrane potential

An ion channel can also open when the receptor is activated by a change in cell potential, that is, the difference of the electrical charge on both sides of the membrane. If such a change occurs, the ion channel of the receptor will open and let ions pass through. In neurons, this mechanism underlies the action potential impulses that travel along nerves.

##### Nuclear receptors

Nuclear (or cytoplasmic) receptors are soluble proteins localized within the cytoplasm or the nucleoplasm. The hormone has to pass through the plasma membrane, usually by passive diffusion, to reach the receptor and initiate the signal cascade. The nuclear receptors are ligand-activated transcription activators; on binding with the ligand (the hormone), they will pass through the nuclear membrane into the nucleus and enable the production of a certain gene and, thus, the production of a protein.

The typical ligands for nuclear receptors are lipophilic hormones, with steroid hormones (for example, testosterone, progesterone and cortisol) and derivatives of vitamin A and D among them. These hormones play a key role in the regulation of metabolism, organ function, developmental processes and cell differentiation. The key value for the signal strength is the hormone concentration, which is regulated by :

• Biosynthesis and secretion of hormones in the endocrine tissue. As an example, the hypothalamus receives information, both electrical and chemical. It produces releasing factors that affect the hypophysis and make it produce glandotrope hormones which, in turn, activate endocrine organs so that they finally produce hormones for the target tissues. This hierarchical system allows for the amplification of the original signal that reached the hypothalamus. The released hormones dampen the production of these hormones by feedback inhibition to avoid overproduction.
• Availability of the hormone in the cytosol. Several hormones can be converted into a storage form by the target cell for later use. This reduces the amount of available hormone.
• Modification of the hormone in the target tissue. Some hormones can be modified by the target cell so they no longer trigger the hormone receptor (or at least, not the same one), effectively reducing the amount of available hormone.

The nuclear receptors that were activated by the hormones attach at the DNA at receptor-specific Hormone Responsive Elements (HREs), DNA sequences that are located in the promoter region of the genes that are activated by the hormone-receptor complex. As this enables the transcription of the according gene, these hormones are also called inductors of gene expression. The activation of gene transcription is much slower than signals that directly affect existing proteins. As a consequence, the effects of hormones that use nucleic receptors are usually long-term. Although the signal transduction via these soluble receptors involves only a few proteins, the details of gene regulation are yet not well understood. The nucleic receptors all have a similar, modular structure:

    N-AAAABBBBCCCCDDDDEEEEFFFF-C

where CCCC is the DNA-binding domain that contains zinc fingers, and EEEE the ligand-binding domain. The latter is also responsible for dimerization of most nuclearic receptors prior to DNA binding. As a third function, it contains structural elements that are responsible for transactivation, used for communication with the translational apparatus. The zinc fingers in the DNA-binding domain stabilize DNA binding by holding contact to the phosphate backbone of the DNA. The DNA sequences that match the receptor are usually hexameric repeats, either normal, inverted or everted. The sequences are quite similar, but their orientation and distance are the parameters by which the DNA-binding domains of the receptors can tell them apart.

##### Steroid receptors

Steroid receptors are a subclass of nuclear receptors, located primarily within the cytosol. In the absence of steroid hormone, the receptors cling together in a complex called aporeceptor complex, which also contains chaperone proteins (also known as heatshock proteins or Hsps). The Hsps are necessary to activate the receptor by assisting the protein to fold in a way such that the signal sequence which enables its passage into the nucleus is accessible. Steroid receptors can also have a repressive effect on gene expression, when their transactivation domain is hidden so it cannot activate transcription. Furthermore, steroid receptor activity can be enhanced by phosphorylation of serine residues at their N-terminal end, as a result of another signal transduction pathway, for example, a by a growth factor. This behaviour is called crosstalk.

##### RXR- and orphan-receptors

These nuclear receptors can be activated by

• a classic endocrine-synthesized hormone that entered the cell by diffusion.
• a hormone that was built within the cell (for example, retinol) from a precursor or prohormone, which can be brought to the cell through the bloodstream.
• a hormone that was completely synthesized within the cell, for example, prostaglandin.

These receptors are located in the nucleus and are not accompanied by chaperone proteins. In the absence of hormone, they bind to their specific DNA sequence, repressing the gene. Upon activation by the hormone, they activate the transcription of the gene they were repressing.

#### Signal amplification

A principle of signal transduction is the signal amplification. The binding of one or a few neurotransmitter molecules can enable the entry of millions of ions. The binding of one or just a few hormone molecules can induce an enzymatic reaction that affect many substrates. The amplification can occur at several points of the signal pathway.

##### Signal amplification at the transmembrane hormone

receptor

A receptor that has been activated by a hormone can activate many downstream effector proteins. For example, a rhodopsin molecule in the plasma membrane of a retina cell in the eye that was activated by a photon can activate up to 2000 effector molecules (in this case, transducin) per second. The total strength of signal amplification by a receptor is determined by:

• The lifetime of the hormone-receptor-complex. The more stable the hormone-receptor-complex is, the less likely the hormone dissociates from the receptor, the longer the receptor will remain active, thus activate more effector proteins.
• The amount and lifetime of the receptor-effector protein-complex. The more effector protein is available to be activated by the receptor, and the faster the activated effector protein can dissociate from the receptor, the more effector protein will be activates in the same amount of time.
• Deactivation of the activated receptor. A receptor that is engaged in a hormone-receptor-complex can be deactivated, either by covalent modification (for example, phosphorylation), or by internalization (see ubiquitin).
##### Intracellular signal transduction

Intracellular signal transduction is largely carried out by second messenger molecules. 

Ca2+ as a second messenger

Ca2+ acts as a signal molecule within the cell. This works by tightly limiting the time and space when Ca2+ is free (and thus active). Therefore, the concentration of free Ca2+ within the cell is usually very low; it is stored within organelles, usually the endoplasmic reticulum (sarcoplasmic reticulum in muscle cells), where it is bound to molecules like calreticulin. 

##### Activation of Ca2+

To become active, Ca2+ has to be released from the endoplasmic reticulum into the cytosol. There are two combined receptor/ion channel proteins that perform the task of controlled transport of Ca2+:

• The InsP3-receptor will transport Ca2+ upon interaction with inositol triphosphate (thus the name) on its cytosolic side. It consists of four identical subunits.
• The ryanodine receptor is named after the plant alkaloid ryanodine. It is similar to the InsP3 receptor and stimulated to transport Ca2+ into the cytosol by recognizing Ca2+ on its cytosolic side, thus establishing a feedback mechanism; a small amount of Ca2+ in the cytosol near the receptor will cause it to release even more Ca2+. It is especially important in neurons and muscle cells. In heart and pancreas cells, another second messenger (cyclic ADP ribose) takes part in the receptor activation.

The localized and time-limited activity of Ca2+ in the cytosol is also called a Ca2+ wave. The building of the wave is done by

• the feedback mechanism of the ryanodine receptor and
• the activation of phospholipase C by Ca2+, which leads to the production of inositol triphosphate, which in turn activates the InsP3 receptor.
##### Function of Ca2+

Ca2+ is used in a multitude of processes, among them muscle contraction, release of neurotransmitter from nerve endings, vision in retina cells, proliferation, secretion, cytoskeleton management, cell migration, gene expression and metabolism. The three main pathways that lead to Ca2+ activation are :

1. G protein regulated pathways
2. Pathways regulated by receptor-tyrosine kinases
3. Ligand- or current-regulated ion channels

There are two different ways in which Ca2+ can regulate proteins:

1. A direct recognition of Ca2+ by the protein.
2. Binding of Ca2+ in the active site of an enzyme

One of the best studied interactions of Ca2+ with a protein is the regulation of calmodulin by Ca2+. Calmodulin itself can regulate other proteins, or be part of a larger protein (for example, phosphorylase kinase). The Ca2+/calmodulin complex plays an important role in proliferation, mitosis and neural signal transduction.

#### Lipophilic second messenger molecules

One group of lipophilic second messenger molecules consists of inositol triphosphate and diacylglycerol. Others are ceramide and lysophosphatic acid.

#### Nitric oxide (NO) as second messenger

The gas nitric oxide is a free radical which diffuses through the plasma membrane and affects nearby cells. NO is made from arginine and oxygen by the enzyme NO synthase, with citrulline as a by-product. NO works mainly through activation of its target receptor, the enzyme soluble guanylate cyclase, which when activated, produces the second messenger cyclic guanosine monophosphate (cGMP). NO can also act through covalent modification of proteins or their metal cofactors. Some of these modifications are reversible and work through a redox mechanism. In high concentrations, NO is toxic, and is thought to be responsible for some damage after a stroke. NO serves three main functions:

1. Relaxation of blood vessels.
2. Regulation of exocytosis of neurotransmitters.
3. Cellular immune response.

#### Hormones

Most of the molecules that enable signalling between the cells or tissues within an individual animal or plant are known as "hormones." Hormone-initiated signal transduction takes the following steps:

1. Biosynthesis of a hormone.
2. Storage and secretion of the hormone.
3. Transport of the hormone to the target cell.
4. Recognition of the hormone by the hormone receptor protein, leading to a conformational change.
5. Relay and amplification of the signal that leads to defined biochemical reactions within the target cell. The reactions of the target cells can, in turn, cause a signal to the hormone-producing cell that leads to the down-regulation of hormone production.
6. Removal of the hormone.

Hormones and other signaling molecules may exit the sending cell by exocytosis or other means of membrane transport. The sending cell is typically of a specialized type. Its recipients may be of one type or several, as in the case of insulin, which triggers diverse and systemic effects.

Hormone signaling is elaborate and hard to dissect. A cell can have several different receptors that recognize the same hormone, but activate different signal transduction pathways; or different hormones and their receptors can invoke the same biochemical pathway. Different tissue types can answer differently to the same hormone stimulus. There are two classes of hormone receptors, "membrane-associated receptors" and intracellular or "cytoplasmic" receptors.