Copyright © Philip M. Parker, INSEAD. Terms of Use.

STIMULI

Definition: STIMULI

STIMULI

Plural

1. Of Stimulus

Source: Webster's Revised Unabridged Dictionary (1913)
 

Date "STIMULI" was first used in popular English literature: sometime before 1785. (references)

 

Specialty Definition: Signal transduction

(From Wikipedia, the free Encyclopedia)

In biology, signal transduction is a cellular response to the surrounding chemicals and the following production of signalling molecules inside of the cell. Signal transduction is a part of nutrient sensing in single cell organisms and cell-cell communication in multicellular organisms. It also mediates sensing of tastes and smells. Signal transduction is usually mediated by cell surface receptors.

More technically signal transduction refers to the transformation of the extracellular physiochemical signals into intracellular signals. Extracellular signals are generally ligands of transmembrane receptors and are generally derived from either other cells or the environment (with the exception of autocrine factors), while an intracellular signal consists of a series of chemical interactions in either the cellular membrane or the intracellular space, or from the cellular membrane to the intracellular space. Generally autocrine factors are secreted from the cell and lose the distinction from those from the neighbouring cells.

Some typical examples of extracellular signals to which unicellular organisms respond include nutrients and related chemicals, while signals to cells in vertebrates organisms include photons, hormones, growth factors, cytokines, interleukins, neurotransmitters and the various ligands of the olfactory and gustatory receptors. Most extracellular chemical signals are water-soluble and membrane impermeable. These molecules act as ligands for transmembrane receptors and cause a structural change in these receptor molecules, which then induces the intracellular signalling phase. Typical examples of membrane permeable and extracellular signals are steroid hormones. Steroids hormones first diffuse into the cell membrane and then bind to their receptors, which are usually located in the cell nucleus.

Intercellular signalling molecules in eukaryotic cells include heterotrimeric G protein, small GTPases, cyclic nucleotides, such as cAMP and cGMP, calcium ion, phophoinositide derivatives, such as Phosphatidylinositol-triphosphate(PIP3), Diacylglycerol (DAG) and Inositol-triphosphate (IP3), and various protein kinases and phosphatases. Intracellular signalling usually leads to certain cellular responses, such as the regulation of gene expression, the modulation of signal transduction pathways, chemotaxis and morphological changes.

Overview and context

Many events can impinge upon a cells: they can be exposed to various chemicals, they can be heated and cooled, hit by photons of various frequencies, or stretched, sheared or electrified. Cells are also sensitive to some of these events; they respond to them in characteristic, and generally adaptive, ways. The process linking the detection of certain kinds of external events to biochemical responses on the part of the cell is called signal transduction, even when the events aren't what one might plausibly think of as "signals".

Two very important kinds of responses cells can make to signals are to change what and how they metabolize molecules, and how much of which of their genes they are expressing. Signal transduction can directly and indirectly affect both. Since genes are expressed as proteins, and many proteins are enzymes, control of metabolism and the regulation of gene expression are intimately linked, though one can be altered without (immediate) affecting the other. Sometimes metabolic control aims at homeostasis -- at maintaining constant levels of some variables, or constant rates of some processes -- but not always; sometimes adaptation demands change. (See gene expression and metabolism for discussion of these networks).

When considering signal transduction pathways and networks, outstanding questions researchers are addressing include:

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: 

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-associated receptors and soluble, cytoplasmic 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 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 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 anchorss, 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 :  
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 
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:  

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


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 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
 
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. 
    

Further information


See also




INDEX
 1. Definition 
 2. Crosswords 
 3. Usage: Commercial 
 4. Quotations: Non-fiction 		 5. Usage Frequency 
 6. Expressions 
 7. Translations: Modern 
 8. Bible Trace 		 9. Derivations 
 10. Rhymes 
 11. Anagrams 
 12. Bibliography 


  
Copyright ©  Philip M. Parker, INSEAD. Terms of Use.