Signal transduction

In biology, signal transduction describes the uptake of environmental signals by cells, the intercellular communication between cells in a multicellular organism, and the signal recognition, transmission, and resulting action within a cell. A typical signal transduction pathway consists of 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.
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.

The signal transduction can be altered at any of these steps. The single most important mechanism to do this is phosphorylation.

Table of contents 1 Processing of environmental signals 2 Intercellular communication 3 Signal recognition 3.1 Hormone receptors 3.1.1 Transmembrane receptors 3.1.1.1 Hormone recognition by transmembrane receptors 3.1.1.2 Signal transduction of transmembrane receptors by structural changes 3.1.1.3 Signal transduction of transmembrane receptors that are ion channels 3.1.1.4 Signal transduction of transmembrane receptors on change of transmembrane potential 3.1.2 Nuclear receptors 3.1.2.1 Steroid receptors 3.1.2.2 RXR- and orphan-receptors 4 Signal amplification 4.1 Signal amplification at the transmembrane hormone receptor 5 Intracellular signal transduction 5.1 Ca2+ as a second messenger 5.1.1 Activation of Ca2+ 5.1.2 Function of Ca2+ 5.2 Lipophilic[?] second messenger molecules 5.3 Nitric oxide (NO) as second messenger

Processing of environmental signals

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Intercellular communication

The communication between cells can be established using

1. Contact via surface proteins
2. Diffusable molecules such as hormones, neurotransmitters and (in cells linked by Gap junctions[?] ) second messengers.

Signaling molecules may exit the sending cell by exocytosis or other means of membrane transport. Their reception may be blocked; for example, hormone antagonists inhibit signalling by binding to a hormone's receptors in or on the target cell.
Intercellular signal transduction can be categorized in the following cases:

• Endocrine signals are produced by special endocrine cells[?] that use exocytosis to bring the hormones into the bloodstream. The signal reaches virtually every cell in the body.
• Paracrine signals are emitted by diffusion and target only cells in the vicinity of the emitting cell. The emitted hormones are also called tissue hormones. A special case of paracrine signals are synapses, that transmit the signal via neurotransmitters only across a very short distance, to a single receptor cell.
• 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.

Signal recognition

The signals from other cells have to be recognized by the recipient cell to be processed so they can lead to action. The recognition is usually done by specialized receptors.

Hormone receptors

Hormones are usually produced only in specialized cells and trigger a response only in certain cell types, that is, those cells that have a receptor for that specific hormone. The binding of the hormone to the hormone receptor initiates a cascade of intracellular transductions of that signal, that ends in a defined biochemical action. The system of hormones and hormone receptors can show a great variability. 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-bound receptors and soluble, cytoplasmic receptors.

Transmembrane receptors

Transmembrane receptors are proteins that pass through 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. The hormone itself does not have to pass through the plasma membrane into the cell.

Hormone recognition by transmembrane receptors

The recognition of the chemical structure of a hormone by the hormone receptor uses the same (non-covalent[?]) mechanisms, such as hydrogen bonds, electrostatic[?] forces, hydrophobe and Van der Waals forces. The equivalent between receptor-bound and free hormone equals [H] + [R] <-> [HR], with

KD =	[H] * [R] (receptor [R] and free hormone [H]) [HR] (receptor-bound hormone [HR])

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 to 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. 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 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 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 lipophile[?] hormones, with steroid hormones (for example, testosterone, progesterone and cortisol[?]) and the vitamins 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 hypophyse[?](???) 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 nuclearic 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 nuclearic 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 nucleric receptors can be activated by

• a classic endocrine-synthesized hormone that entered the cell by diffusion.
• a hormone that was build 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. A single or 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 therefore, 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 inosite triphosphate (thus the name) on its cytosolic side. It consists of four identical subunits.
• The ryanodin-receptor is named after the plant alkaloid ryanodin[?]. 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 ryanodin 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, vision in retina cells, proliferation[?], secretion[?], cytoskeleton management, cell motion[?], 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 center[?] 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

Nitric oxide is a radical gas whose molecules diffuse through the plasma membrane and affect other, 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.

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See also : G protein-coupled receptor -- GTPases -- Protein phosphatase