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 "signalling cascade " or "second messenger pathway" and the result is that a small stimulus elicits 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.
3.1.1 Hormone recognition by transmembrane receptors
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 that allow nerve cells to communicate across synapses, bind to receptor proteins in the membrane and open their ion channels.
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 panoply of physiolgical 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.
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 have affinity for water and are unable to penetrate the oily barrier posed by the membrane that surrounds cells. A common kind of extracellular signal is nutrient. In complex organism 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 of a partial affinity for oily surroundings (see hydrophobic).
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 communication is accomplished by extracellular signalling and takes place in complex organisms that are composed of many cells. Within endocrinology, which is the study of intercellular signalling in animals, intercellular signalling is subdivided into the following types:
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:
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 recipents may be of one type or several, as in the case of insulin, which triggers diverse and systemic effects.
Hormones signalling 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.
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.
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
[R]=receptor; [H]=free hormone; [HR]=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 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.
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.
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 (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:
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 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.
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.
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.
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 is largely carried out by second messenger molecules.
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.
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
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 :
There are two different ways in which Ca2+ can regulate proteins:
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.
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:
When considering signal transduction pathways and networks, outstanding questions researchers are addressing include: