Information

12.4.3: Propagation of the Signal - Biology


Skills to Develop

  • Explain how the binding of a ligand initiates signal transduction throughout a cell
  • Recognize the role of phosphorylation in the transmission of intracellular signals
  • Evaluate the role of second messengers in signal transmission

Once a ligand binds to a receptor, the signal is transmitted through the membrane and into the cytoplasm. Signal transduction only occurs with cell-surface receptors because internal receptors are able to interact directly with DNA in the nucleus to initiate protein synthesis.

When a ligand binds to its receptor, conformational changes occur that affect the receptor’s intracellular domain. Conformational changes of the extracellular domain upon ligand binding can propagate through the membrane region of the receptor and lead to activation of the intracellular domain or its associated proteins. In some cases, binding of the ligand causes dimerization of the receptor, which means that two receptors bind to each other to form a stable complex called a dimer. A dimer is a chemical compound formed when two molecules (often identical) join together. The binding of the receptors in this manner enables their intracellular domains to come into close contact and activate each other.

Binding Initiates a Signaling Pathway

After the ligand binds to the cell-surface receptor, the activation of the receptor’s intracellular components sets off a chain of events that is called a signaling pathway or a signaling cascade. In a signaling pathway, second messengers, enzymes, and activated proteins interact with specific proteins, which are in turn activated in a chain reaction that eventually leads to a change in the cell’s environment (Figure (PageIndex{1})). The events in the cascade occur in a series, much like a current flows in a river. Interactions that occur before a certain point are defined as upstream events, and events after that point are called downstream events.

Art Connection

In certain cancers, the GTPase activity of the RAS G-protein is inhibited. This means that the RAS protein can no longer hydrolyze GTP into GDP. What effect would this have on downstream cellular events?

Signaling pathways can get very complicated very quickly because most cellular proteins can affect different downstream events, depending on the conditions within the cell. A single pathway can branch off toward different endpoints based on the interplay between two or more signaling pathways, and the same ligands are often used to initiate different signals in different cell types. This variation in response is due to differences in protein expression in different cell types. Another complicating element is signal integration of the pathways, in which signals from two or more different cell-surface receptors merge to activate the same response in the cell. This process can ensure that multiple external requirements are met before a cell commits to a specific response.

The effects of extracellular signals can also be amplified by enzymatic cascades. At the initiation of the signal, a single ligand binds to a single receptor. However, activation of a receptor-linked enzyme can activate many copies of a component of the signaling cascade, which amplifies the signal.

Methods of Intracellular Signaling

The induction of a signaling pathway depends on the modification of a cellular component by an enzyme. There are numerous enzymatic modifications that can occur, and they are recognized in turn by the next component downstream. The following are some of the more common events in intracellular signaling.

One of the most common chemical modifications that occurs in signaling pathways is the addition of a phosphate group (PO4–3) to a molecule such as a protein in a process called phosphorylation. The phosphate can be added to a nucleotide such as GMP to form GDP or GTP. Phosphates are also often added to serine, threonine, and tyrosine residues of proteins, where they replace the hydroxyl group of the amino acid (Figure (PageIndex{2})). The transfer of the phosphate is catalyzed by an enzyme called a kinase. Various kinases are named for the substrate they phosphorylate. Phosphorylation of serine and threonine residues often activates enzymes. Phosphorylation of tyrosine residues can either affect the activity of an enzyme or create a binding site that interacts with downstream components in the signaling cascade. Phosphorylation may activate or inactivate enzymes, and the reversal of phosphorylation, dephosphorylation by a phosphatase, will reverse the effect.

Second Messengers

Second messengers are small molecules that propagate a signal after it has been initiated by the binding of the signaling molecule to the receptor. These molecules help to spread a signal through the cytoplasm by altering the behavior of certain cellular proteins.

Calcium ion is a widely used second messenger. The free concentration of calcium ions (Ca2+) within a cell is very low because ion pumps in the plasma membrane continuously use adenosine-5'-triphosphate (ATP) to remove it. For signaling purposes, Ca2+ is stored in cytoplasmic vesicles, such as the endoplasmic reticulum, or accessed from outside the cell. When signaling occurs, ligand-gated calcium ion channels allow the higher levels of Ca2+ that are present outside the cell (or in intracellular storage compartments) to flow into the cytoplasm, which raises the concentration of cytoplasmic Ca2+. The response to the increase in Ca2+ varies, depending on the cell type involved. For example, in the β-cells of the pancreas, Ca2+ signaling leads to the release of insulin, and in muscle cells, an increase in Ca2+ leads to muscle contractions.

Another second messenger utilized in many different cell types is cyclic AMP (cAMP). Cyclic AMP is synthesized by the enzyme adenylyl cyclase from ATP (Figure (PageIndex{3})). The main role of cAMP in cells is to bind to and activate an enzyme called cAMP-dependent kinase (A-kinase). A-kinase regulates many vital metabolic pathways: It phosphorylates serine and threonine residues of its target proteins, activating them in the process. A-kinase is found in many different types of cells, and the target proteins in each kind of cell are different. Differences give rise to the variation of the responses to cAMP in different cells.

Present in small concentrations in the plasma membrane, inositol phospholipids are lipids that can also be converted into second messengers. Because these molecules are membrane components, they are located near membrane-bound receptors and can easily interact with them. Phosphatidylinositol (PI) is the main phospholipid that plays a role in cellular signaling. Enzymes known as kinases phosphorylate PI to form PI-phosphate (PIP) and PI-bisphosphate (PIP2).

The enzyme phospholipase C cleaves PIP2 to form diacylglycerol (DAG) and inositol triphosphate (IP3) (Figure (PageIndex{4})). These products of the cleavage of PIP2 serve as second messengers. Diacylglycerol (DAG) remains in the plasma membrane and activates protein kinase C (PKC), which then phosphorylates serine and threonine residues in its target proteins. IP3 diffuses into the cytoplasm and binds to ligand-gated calcium channels in the endoplasmic reticulum to release Ca2+ that continues the signal cascade.

Summary

Ligand binding to the receptor allows for signal transduction through the cell. The chain of events that conveys the signal through the cell is called a signaling pathway or cascade. Signaling pathways are often very complex because of the interplay between different proteins. A major component of cell signaling cascades is the phosphorylation of molecules by enzymes known as kinases. Phosphorylation adds a phosphate group to serine, threonine, and tyrosine residues in a protein, changing their shapes, and activating or inactivating the protein. Small molecules like nucleotides can also be phosphorylated. Second messengers are small, non-protein molecules that are used to transmit a signal within a cell. Some examples of second messengers are calcium ions (Ca2+), cyclic AMP (cAMP), diacylglycerol (DAG), and inositol triphosphate (IP3).

Art Connections

[link] In certain cancers, the GTPase activity of the RAS G-protein is inhibited. What effect would this have on downstream cellular events?

[link] ERK would become permanently activated, resulting in cell proliferation, migration, adhesion, and the growth of new blood vessels. Apoptosis would be inhibited.

Glossary

cyclic AMP (cAMP)
second messenger that is derived from ATP
cyclic AMP-dependent kinase
(also, protein kinase A, or PKA) kinase that is activated by binding to cAMP
diacylglycerol (DAG)
cleavage product of PIP2 that is used for signaling within the plasma membrane
dimer
chemical compound formed when two molecules join together
dimerization
(of receptor proteins) interaction of two receptor proteins to form a functional complex called a dimer
inositol phospholipid
lipid present at small concentrations in the plasma membrane that is converted into a second messenger; it has inositol (a carbohydrate) as its hydrophilic head group
inositol triphosphate (IP3)
cleavage product of PIP2 that is used for signaling within the cell
kinase
enzyme that catalyzes the transfer of a phosphate group from ATP to another molecule
second messenger
small, non-protein molecule that propagates a signal within the cell after activation of a receptor causes its release
signal integration
interaction of signals from two or more different cell-surface receptors that merge to activate the same response in the cell
signal transduction
propagation of the signal through the cytoplasm (and sometimes also the nucleus) of the cell
signaling pathway
(also signaling cascade) chain of events that occurs in the cytoplasm of the cell to propagate the signal from the plasma membrane to produce a response

Nuclear localization sequence

A nuclear localization signal or sequence (NLS) is an amino acid sequence that 'tags' a protein for import into the cell nucleus by nuclear transport. [1] Typically, this signal consists of one or more short sequences of positively charged lysines or arginines exposed on the protein surface. [1] Different nuclear localized proteins may share the same NLS. [1] An NLS has the opposite function of a nuclear export signal (NES), which targets proteins out of the nucleus.


Second Messengers

Second messengers are small molecules that propagate a signal after it has been initiated by the binding of the signaling molecule to the receptor. These molecules help to spread a signal through the cytoplasm by altering the behavior of certain cellular proteins.

Calcium ion is a widely used second messenger. The free concentration of calcium ions (Ca 2+ ) within a cell is very low because ion pumps in the plasma membrane continuously use adenosine-5'-triphosphate (ATP) to remove it. For signaling purposes, Ca 2+ is stored in cytoplasmic vesicles, such as the endoplasmic reticulum, or accessed from outside the cell. When signaling occurs, ligand-gated calcium ion channels allow the higher levels of Ca 2+ that are present outside the cell (or in intracellular storage compartments) to flow into the cytoplasm, which raises the concentration of cytoplasmic Ca 2+ . The response to the increase in Ca 2+ varies, depending on the cell type involved. For example, in the β-cells of the pancreas, Ca 2+ signaling leads to the release of insulin, and in muscle cells, an increase in Ca 2+ leads to muscle contractions.

Another second messenger utilized in many different cell types is cyclic AMP (cAMP) . Cyclic AMP is synthesized by the enzyme adenylyl cyclase from ATP (Figure). The main role of cAMP in cells is to bind to and activate an enzyme called cAMP-dependent kinase (A-kinase). A-kinase regulates many vital metabolic pathways: It phosphorylates serine and threonine residues of its target proteins, activating them in the process. A-kinase is found in many different types of cells, and the target proteins in each kind of cell are different. Differences give rise to the variation of the responses to cAMP in different cells.

This diagram shows the mechanism for the formation of cyclic AMP (cAMP). cAMP serves as a second messenger to activate or inactivate proteins within the cell. Termination of the signal occurs when an enzyme called phosphodiesterase converts cAMP into AMP.

Present in small concentrations in the plasma membrane, inositol phospholipids are lipids that can also be converted into second messengers. Because these molecules are membrane components, they are located near membrane-bound receptors and can easily interact with them. Phosphatidylinositol (PI) is the main phospholipid that plays a role in cellular signaling. Enzymes known as kinases phosphorylate PI to form PI-phosphate (PIP) and PI-bisphosphate (PIP2).

The enzyme phospholipase C cleaves PIP2 to form diacylglycerol (DAG) and inositol triphosphate (IP3) (Figure). These products of the cleavage of PIP2 serve as second messengers. Diacylglycerol (DAG) remains in the plasma membrane and activates protein kinase C (PKC), which then phosphorylates serine and threonine residues in its target proteins. IP3 diffuses into the cytoplasm and binds to ligand-gated calcium channels in the endoplasmic reticulum to release Ca 2+ that continues the signal cascade.

The enzyme phospholipase C breaks down PIP2 into IP3 and DAG, both of which serve as second messengers.


Review Questions

What property enables the residues of the amino acids serine, threonine, and tyrosine to be phosphorylated?

  1. They are polar.
  2. They are non-polar.
  3. They contain a hydroxyl group.
  4. They occur more frequently in the amino acid sequence of signaling proteins.

Histamine binds to the H1 G-protein-linked receptor to initiate the itchiness and airway constriction associated with an allergic response. If a mutation in the associated G-protein’s alpha subunit prevented the hydrolysis of GTP how would the allergic response change?

  1. More severe allergic response compared to normal G-protein signaling.
  2. Less severe allergic response compared to normal G-protein signaling.
  3. No allergic response.
  4. No change compared to normal G-protein signaling.

A scientist observes a mutation in the transmembrane region of EGFR that eliminates its ability to be stabilized by binding interactions during dimerization after ligand binding. Which hypothesis regarding the effect of this mutation on EGF signaling is most likely to be correct?


Methods of Intracellular Signaling

Signaling pathway induction activates a sequence of enzymatic modifications that are recognized in turn by the next component downstream.

Learning Objectives

Explain how the binding of a ligand initiates signal transduction throughout a cell

Key Takeaways

Key Points

  • Phosphorylation, the addition of a phosphate group to a molecule such as a protein, is one of the most common chemical modifications that occurs in signaling pathways.
  • The activation of second messengers, small molecules that propagate a signal, is a common event after the induction of a signaling pathway.
  • Calcium ion, cyclic AMP, and inositol phospholipids are examples of widely-used second messengers.

Key Terms

  • second messenger: any substance used to transmit a signal within a cell, especially one which triggers a cascade of events by activating cellular components
  • phosphorylation: the addition of a phosphate group to a compound often catalyzed by enzymes

The induction of a signaling pathway depends on the modification of a cellular component by an enzyme. There are numerous enzymatic modifications that can occur which are recognized in turn by the next component downstream.

One of the most common chemical modifications that occurs in signaling pathways is the addition of a phosphate group (PO4 –3 ) to a molecule such as a protein in a process called phosphorylation. The phosphate can be added to a nucleotide such as GMP to form GDP or GTP. Phosphates are also often added to serine, threonine, and tyrosine residues of proteins where they replace the hydroxyl group of the amino acid. The transfer of the phosphate is catalyzed by an enzyme called a kinase. Various kinases are named for the substrate they phosphorylate. Phosphorylation of serine and threonine residues often activates enzymes. Phosphorylation of tyrosine residues can either affect the activity of an enzyme or create a binding site that interacts with downstream components in the signaling cascade. Phosphorylation may activate or inactivate enzymes the reversal of phosphorylation, dephosphorylation by a phosphatase, will reverse the effect.

Example of phosphorylation: In protein phosphorylation, a phosphate group (PO4-3 ) is added to residues of the amino acids serine, threonine, and tyrosine.

The activation of second messengers is also a common event after the induction of a signaling pathway. They are small molecules that propagate a signal after it has been initiated by the binding of the signaling molecule to the receptor. These molecules help to spread a signal through the cytoplasm by altering the behavior of certain cellular proteins.

Calcium ion is a widely-used second messenger. The free concentration of calcium ions (Ca 2+ ) within a cell is very low because ion pumps in the plasma membrane continuously use adenosine-5′-triphosphate ( ATP ) to remove it. For signaling purposes, Ca 2+ is stored in cytoplasmic vesicles, such as the endoplasmic reticulum, or accessed from outside the cell. When signaling occurs, ligand-gated calcium ion channels allow the higher levels of Ca 2+ that are present outside the cell (or in intracellular storage compartments) to flow into the cytoplasm, which raises the concentration of cytoplasmic Ca 2+ . The response to the increase in Ca 2+ varies, depending on the cell type involved. For example, in the β-cells of the pancreas, Ca 2+ signaling leads to the release of insulin, whereas in muscle cells, an increase in Ca 2+ leads to muscle contractions.

Another second messenger utilized in many different cell types is cyclic AMP (cAMP). Cyclic AMP is synthesized by the enzyme adenylyl cyclase from ATP. The main role of cAMP in cells is to bind to and activate an enzyme called cAMP-dependent kinase (A-kinase). A-kinase regulates many vital metabolic pathways. It phosphorylates serine and threonine residues of its target proteins, activating them in the process. A-kinase is found in many different types of cells the target proteins in each kind of cell are different. Differences give rise to the variation of the responses to cAMP in different cells.

Example of cAMP as a second messenger: This diagram shows the mechanism for the formation of cyclic AMP (cAMP). cAMP serves as a second messenger to activate or inactivate proteins within the cell. Termination of the signal occurs when an enzyme called phosphodiesterase converts cAMP into AMP.

Present in small concentrations in the plasma membrane, inositol phospholipids are lipids that can also be converted into second messengers. Because these molecules are membrane components, they are located near membrane-bound receptors and can easily interact with them. Phosphatidylinositol (PI) is the main phospholipid that plays a role in cellular signaling. Enzymes known as kinases phosphorylate PI to form PI-phosphate (PIP) and PI-bisphosphate (PIP2).


Cell Death

When a cell is damaged, superfluous, or potentially dangerous to an organism, a cell can initiate a mechanism to trigger programmed cell death, or apoptosis. Apoptosis allows a cell to die in a controlled manner that prevents the release of potentially damaging molecules from inside the cell. There are many internal checkpoints that monitor a cell’s health if abnormalities are observed, a cell can spontaneously initiate the process of apoptosis. However, in some cases, such as a viral infection or uncontrolled cell division due to cancer, the cell’s normal checks and balances fail. External signaling can also initiate apoptosis. For example, most normal animal cells have receptors that interact with the extracellular matrix, a network of glycoproteins that provides structural support for cells in an organism. The binding of cellular receptors to the extracellular matrix initiates a signaling cascade within the cell. However, if the cell moves away from the extracellular matrix, the signaling ceases, and the cell undergoes apoptosis. This system keeps cells from traveling through the body and proliferating out of control, as happens with tumor cells that metastasize.

Another example of external signaling that leads to apoptosis occurs in T-cell development. T-cells are immune cells that bind to foreign macromolecules and particles, and target them for destruction by the immune system. Normally, T-cells do not target “self” proteins (those of their own organism), a process that can lead to autoimmune diseases. In order to develop the ability to discriminate between self and non-self, immature T-cells undergo screening to determine whether they bind to so-called self proteins. If the T-cell receptor binds to self proteins, the cell initiates apoptosis to remove the potentially dangerous cell.

Apoptosis is also essential for normal embryological development. In vertebrates, for example, early stages of development include the formation of web-like tissue between individual fingers and toes (Figure 2). During the course of normal development, these unneeded cells must be eliminated, enabling fully separated fingers and toes to form. A cell signaling mechanism triggers apoptosis, which destroys the cells between the developing digits.

Figure 2 The histological section of a foot of a 15-day-old mouse embryo, visualized using light microscopy, reveals areas of tissue between the toes, which apoptosis will eliminate before the mouse reaches its full gestational age at 27 days. (credit: modification of work by Michal Mañas)


Energy for Muscle Contraction

According to the sliding filament theory, ATP is needed to provide the energy for a muscle contraction. Where does this ATP come from? Actually, there are multiple potential sources, as illustrated in Figure 12.4.5 below.

  1. As you can see from the first diagram, some ATP is already available in a resting muscle. As a muscle contraction starts, this ATP is used up in just a few seconds. More ATP is generated from creatine phosphate , but this ATP is used up rapidly as well. It’s gone in another 15 seconds or so.
  2. Glucose from the blood and glycogen stored in muscle can then be used to make more ATP. Glycogen breaks down to form glucose, and each glucose molecule produces two molecules of ATP and two molecules of pyruvate. Pyruvate (as pyruvic acid) can be used in aerobic respiration if oxygen is available. Alternatively, pyruvate can be used in anaerobic respiration , if oxygen is not available. The latter produces lactic acid, which may contribute to muscle fatigue. Anaerobic respiration typically occurs only during strenuous exercise when so much ATP is needed that sufficient oxygen cannot be delivered to the muscle to keep up.
  3. Resting or moderately active muscles can get most of the ATP they need for contractions by aerobic respiration. This process takes place in the mitochondria of muscle cells. In the process, glucose and oxygen react to produce carbon dioxide, water, and many molecules of ATP.

Contents

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. [10] 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. [11]

In slime moulds, individual cells known as amoebae aggregate together to form fruiting bodies and eventually spores, under the influence of a chemical signal, originally named 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 other molecules, in its case N-propionyl-gamma-L-glutamyl-L-ornithine-delta-lactam ethyl ester, nicknamed glorin. [12]

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 (e.g., notch signaling). [13] Autocrine signaling is a special case of paracrine signaling where the secreting cell has the ability to respond to the secreted signaling molecule. [14] Synaptic signaling is a special case of paracrine signaling (for chemical synapses) or juxtacrine signaling (for electrical synapses) between neurons and target cells.

Synthesis and release Edit

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 a same molecule can act both via surface receptors or in an intracrine manner to different effects. [14] 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. [15] 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. [16]

Exocytosis Edit

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, 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 means. 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 structure at the cell plasma membrane, where secretory vesicles transiently dock and fuse to release intra-vesicular contents from the cell.

In exocytosis, membrane-bound secretory vesicles are carried to the cell membrane, where they dock and fuse at porosomes and their contents (i.e., water-soluble molecules) are secreted into the extracellular environment. This secretion is possible because the vesicle transiently fuses with the plasma membrane. In the context of neurotransmission, neurotransmitters are typically released from synaptic vesicles into the synaptic cleft via exocytosis however, neurotransmitters can also be released via reverse transport through membrane transport proteins.

Forms Edit

Autocrine Edit

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. [17] This can be contrasted with paracrine signaling, intracrine signaling, or classical endocrine signaling.

Paracrine Edit

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. [18] 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. [19] Estrogen can be released by the ovary and function as a hormone or act locally via paracrine or autocrine signaling. [20]

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. [21] 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 Edit

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.

Juxtacrine Edit

Juxtacrine signaling is a type of cell–cell or cell–extracellular matrix signaling in multicellular organisms that requires close contact. There are three types:

  1. A membrane ligand (protein, oligosaccharide, lipid) and a membrane protein of two adjacent cells interact.
  2. A communicating junction links the intracellular compartments of two adjacent cells, allowing transit of relatively small molecules.
  3. An extracellular matrixglycoprotein 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.

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. [22] In the human gastrointestinal tract, bacteria exchange signals with each other and with human epithelial and immune system cells. [23] 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. [24]

Cell surface receptors Edit

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. [25] 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. By looking at three major types of receptors: Ion channel linked receptors, G protein–coupled receptors, and enzyme-linked receptors).

Ion channel linked receptors Edit

Ion channel linked receptors are a group of transmembrane ion-channel proteins which open to allow ions such as Na + , K + , Ca 2+ , 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. [26] [27] [28]

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, 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 Edit

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. [29] 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. [29]

G protein-coupled receptors are found only in eukaryotes, including yeast, choanoflagellates, [30] 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. [31] 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). [32] : 1160

G protein-coupled receptors are an important drug target and approximately 34% [33] 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 [update] . [33] 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 the pharmaceutical research. [29]

Enzyme-linked receptors Edit

Enzyme-linked receptors (or catalytic receptors) are transmembrane receptor that, upon activation by an extracellular ligand, causes enzymatic activity on the intracellular side. [34] Hence a catalytic receptor is an integral membrane protein possessing both enzymatic, catalytic, and receptor functions. [35]

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 Edit

Steroid hormone receptor Edit

Steroid hormone receptors are found in the nucleus, cytosol, and also on the plasma membrane of target cells. They are generally intracellular receptors (typically cytoplasmic or nuclear) and initiate signal transduction for steroid hormones which lead to changes in gene expression over a time period of hours to days. The best studied steroid hormone receptors are members of the nuclear receptor subfamily 3 (NR3) that include receptors for estrogen (group NR3A) [37] and 3-ketosteroids (group NR3C). [38] In addition to nuclear receptors, several G protein-coupled receptors and ion channels act as cell surface receptors for certain steroid hormones.

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. [15]

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. [39]

A more complex signal transduction pathway is shown in Figure 3. This pathway 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 Figure 3, 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 factor MYC 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. [ citation needed ]

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. [ citation needed ]

Complex multi-component signal transduction pathways provide opportunities for feedback, signal amplification, and interactions inside one cell between multiple signals and signaling pathways. [ citation needed ]

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. [40]

In unicellular organisms such as bacteria, signaling can be used to 'activate' peers from a dormant state, enhance virulence, defend against bacteriophages, etc. [41] 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. [42] [43] [44] This signaling mechanism may have been involved in evolution from unicellular to multicellular organisms. [42] [45] Bacteria also use contact-dependent signaling, notably to limit their growth. [46]

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. [47]

Short-term cellular responses Edit

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) Example of effectors Further downstream effects
Ligand Gated Ion Channels Acetylcholine
(Such as Nicotinic acetylcholine receptor),
Changes in membrane permeability Change in membrane potential
Seven Helix Receptor Light(Rhodopsin),
Dopamine (Dopamine receptor),
GABA (GABA receptor),
Prostaglandin (prostaglandin receptor) etc.
Trimeric G protein Adenylate Cyclase,
cGMP phosphodiesterase,
G-protein gated ion channel, etc.
Two Component Diverse activators Histidine Kinase Response Regulator - flagellar movement, Gene expression
Membrane Guanylyl Cyclase Atrial natriuretic peptide,
Sea urching egg peptide etc.
cGMP Regulation of Kinases and channels- Diverse actions
Cytoplasmic Guanylyl cyclase Nitric Oxide(Nitric oxide receptor) cGMP Regulation of cGMP Gated channels, Kinases
Integrins Fibronectins, other extracellular matrix proteins Nonreceptor tyrosine kinase Diverse response

Regulating gene activity Edit

Brief overview of some signaling pathways (based on receptor families) that control gene activity
Frizzled (Special type of 7Helix receptor) Wnt Dishevelled, axin - APC, GSK3-beta - Beta catenin Gene expression
Two Component Diverse activators Histidine Kinase Response Regulator - flagellar movement, Gene expression
Receptor Tyrosine Kinase Insulin (insulin receptor),
EGF (EGF receptor),
FGF-Alpha, FGF-Beta, etc (FGF-receptors)
Ras, MAP-kinases, PLC, PI3-Kinase Gene expression change
Cytokine receptors Erythropoietin,
Growth Hormone (Growth Hormone Receptor),
IFN-Gamma (IFN-Gamma receptor) etc
JAK kinase STAT transcription factor - Gene expression
Tyrosine kinase Linked- receptors MHC-peptide complex - TCR, Antigens - BCR Cytoplasmic Tyrosine Kinase Gene expression
Receptor Serine/Threonine Kinase Activin(activin receptor),
Inhibin,
Bone-morphogenetic protein(BMP Receptor),
TGF-beta
Smad transcription factors Control of gene expression
Sphingomyelinase linked receptors IL-1(IL-1 receptor),
TNF (TNF-receptors)
Ceramide activated kinases Gene expression
Cytoplasmic Steroid receptors Steroid hormones,
Thyroid hormones,
Retinoic acid etc
Work as/ interact with transcription factors Gene expression

Notch signaling pathway Edit

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. [52] 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. [53] [54] Emerging methods for single-cell mass-spectrometry analysis promise to enable studying signal transduction with single-cell resolution. [55]

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. [56]


46 Propagation of the Signal

By the end of this section, you will be able to do the following:

  • Explain how the binding of a ligand initiates signal transduction throughout a cell
  • Recognize the role of phosphorylation in the transmission of intracellular signals
  • Evaluate the role of second messengers in signal transmission

Once a ligand binds to a receptor, the signal is transmitted through the membrane and into the cytoplasm. Continuation of a signal in this manner is called signal transduction . Signal transduction only occurs with cell-surface receptors, which cannot interact with most components of the cell such as DNA. Only internal receptors are able to interact directly with DNA in the nucleus to initiate protein synthesis.

When a ligand binds to its receptor, conformational changes occur that affect the receptor’s intracellular domain. Conformational changes of the extracellular domain upon ligand binding can propagate through the membrane region of the receptor and lead to activation of the intracellular domain or its associated proteins. In some cases, binding of the ligand causes dimerization of the receptor, which means that two receptors bind to each other to form a stable complex called a dimer. A dimer is a chemical compound formed when two molecules (often identical) join together. The binding of the receptors in this manner enables their intracellular domains to come into close contact and activate each other.

Binding Initiates a Signaling Pathway

After the ligand binds to the cell-surface receptor, the activation of the receptor’s intracellular components sets off a chain of events that is called a signaling pathway , sometimes called a signaling cascade. In a signaling pathway, second messengers–enzymes–and activated proteins interact with specific proteins, which are in turn activated in a chain reaction that eventually leads to a change in the cell’s environment ((Figure)), such as an increase in metabolism or specific gene expression. The events in the cascade occur in a series, much like a current flows in a river. Interactions that occur before a certain point are defined as upstream events, and events after that point are called downstream events.


In certain cancers, the GTPase activity of the RAS G-protein is inhibited. This means that the RAS protein can no longer hydrolyze GTP into GDP. What effect would this have on downstream cellular events?

You can see that signaling pathways can get very complicated very quickly because most cellular proteins can affect different downstream events, depending on the conditions within the cell. A single pathway can branch off toward different endpoints based on the interplay between two or more signaling pathways, and the same ligands are often used to initiate different signals in different cell types. This variation in response is due to differences in protein expression in different cell types. Another complicating element is signal integration of the pathways, in which signals from two or more different cell-surface receptors merge to activate the same response in the cell. This process can ensure that multiple external requirements are met before a cell commits to a specific response.

The effects of extracellular signals can also be amplified by enzymatic cascades. At the initiation of the signal, a single ligand binds to a single receptor. However, activation of a receptor-linked enzyme can activate many copies of a component of the signaling cascade, which amplifies the signal.

Observe an animation of cell signaling at this site.

Methods of Intracellular Signaling

The induction of a signaling pathway depends on the modification of a cellular component by an enzyme. There are numerous enzymatic modifications that can occur, and they are recognized in turn by the next component downstream. The following are some of the more common events in intracellular signaling.

Phosphorylation

One of the most common chemical modifications that occurs in signaling pathways is the addition of a phosphate group (PO4 –3 ) to a molecule such as a protein in a process called phosphorylation. The phosphate can be added to a nucleotide such as GMP to form GDP or GTP. Phosphates are also often added to serine, threonine, and tyrosine residues of proteins, where they replace the hydroxyl group of the amino acid ((Figure)). The transfer of the phosphate is catalyzed by an enzyme called a kinase . Various kinases are named for the substrate they phosphorylate. Phosphorylation of serine and threonine residues often activates enzymes. Phosphorylation of tyrosine residues can either affect the activity of an enzyme or create a binding site that interacts with downstream components in the signaling cascade. Phosphorylation may activate or inactivate enzymes, and the reversal of phosphorylation, dephosphorylation by a phosphatase, will reverse the effect.


Second Messengers

Second messengers are small molecules that propagate a signal after it has been initiated by the binding of the signaling molecule to the receptor. These molecules help to spread a signal through the cytoplasm by altering the behavior of certain cellular proteins.

Calcium ion is a widely used second messenger. The free concentration of calcium ions (Ca 2+ ) within a cell is very low because ion pumps in the plasma membrane continuously remove it by using adenosine-5′-triphosphate (ATP). For signaling purposes, Ca 2+ is stored in cytoplasmic vesicles, such as the endoplasmic reticulum, or accessed from outside the cell. When signaling occurs, ligand-gated calcium ion channels allow the higher levels of Ca 2+ that are present outside the cell (or in intracellular storage compartments) to flow into the cytoplasm, which raises the concentration of cytoplasmic Ca 2+ . The response to the increase in Ca 2+ varies and depends on the cell type involved. For example, in the β-cells of the pancreas, Ca 2+ signaling leads to the release of insulin, and in muscle cells, an increase in Ca 2+ leads to muscle contractions.

Another second messenger utilized in many different cell types is cyclic AMP (cAMP) . Cyclic AMP is synthesized by the enzyme adenylyl cyclase from ATP ((Figure)). The main role of cAMP in cells is to bind to and activate an enzyme called cAMP-dependent kinase (A-kinase) . A-kinase regulates many vital metabolic pathways: It phosphorylates serine and threonine residues of its target proteins, activating them in the process. A-kinase is found in many different types of cells, and the target proteins in each kind of cell are different. Differences give rise to the variation of the responses to cAMP in different cells.


Present in small concentrations in the plasma membrane, inositol phospholipids are lipids that can also be converted into second messengers. Because these molecules are membrane components, they are located near membrane-bound receptors and can easily interact with them. Phosphatidylinositol (PI) is the main phospholipid that plays a role in cellular signaling. Enzymes known as kinases phosphorylate PI to form PI-phosphate (PIP) and PI-bisphosphate (PIP2).

The enzyme phospholipase C cleaves PIP2 to form diacylglycerol (DAG) and inositol triphosphate (IP3) ((Figure)). These products of the cleavage of PIP2 serve as second messengers. Diacylglycerol (DAG) remains in the plasma membrane and activates protein kinase C (PKC), which then phosphorylates serine and threonine residues in its target proteins. IP3 diffuses into the cytoplasm and binds to ligand-gated calcium channels in the endoplasmic reticulum to release Ca 2+ that continues the signal cascade.


Section Summary

Ligand binding to the receptor allows for signal transduction through the cell. The chain of events that conveys the signal through the cell is called a signaling pathway or cascade. Signaling pathways are often very complex because of the interplay between different proteins. A major component of cell signaling cascades is the phosphorylation of molecules by enzymes known as kinases. Phosphorylation adds a phosphate group to serine, threonine, and tyrosine residues in a protein, changing their shapes, and activating or inactivating the protein. Small molecules like nucleotides can also be phosphorylated. Second messengers are small, non-protein molecules that are used to transmit a signal within a cell. Some examples of second messengers are calcium ions (Ca 2+ ), cyclic AMP (cAMP), diacylglycerol (DAG), and inositol triphosphate (IP3).

Visual Connection Questions

(Figure) In certain cancers, the GTPase activity of the RAS G-protein is inhibited. This means that the RAS protein can no longer hydrolyze GTP into GDP. What effect would this have on downstream cellular events?

(Figure) ERK would become permanently activated, resulting in cell proliferation, migration, adhesion, and the growth of new blood vessels. Apoptosis would be inhibited.

Review Questions

Where do DAG and IP3 originate?

  1. They are formed by phosphorylation of cAMP.
  2. They are ligands expressed by signaling cells.
  3. They are hormones that diffuse through the plasma membrane to stimulate protein production.
  4. They are the cleavage products of the inositol phospholipid, PIP2.

What property enables the residues of the amino acids serine, threonine, and tyrosine to be phosphorylated?

  1. They are polar.
  2. They are non-polar.
  3. They contain a hydroxyl group.
  4. They occur more frequently in the amino acid sequence of signaling proteins.

Histamine binds to the H1 G-protein-linked receptor to initiate the itchiness and airway constriction associated with an allergic response. If a mutation in the associated G-protein’s alpha subunit prevented the hydrolysis of GTP how would the allergic response change?

  1. More severe allergic response compared to normal G-protein signaling.
  2. Less severe allergic response compared to normal G-protein signaling.
  3. No allergic response.
  4. No change compared to normal G-protein signaling.

A scientist observes a mutation in the transmembrane region of EGFR that eliminates its ability to be stabilized by binding interactions during dimerization after ligand binding. Which hypothesis regarding the effect of this mutation on EGF signaling is most likely to be correct?

  1. EGF signaling cascades would be active for longer in the cell.
  2. EGF signaling cascades would be active for a shorter period of time in the cell.
  3. EGF signaling cascades would not occur.
  4. EGF signaling would be unaffected.

Critical Thinking Questions

The same second messengers are used in many different cells, but the response to second messengers is different in each cell. How is this possible?

Different cells produce different proteins, including cell-surface receptors and signaling pathway components. Therefore, they respond to different ligands, and the second messengers activate different pathways. Signal integration can also change the end result of signaling.

What would happen if the intracellular domain of a cell-surface receptor was switched with the domain from another receptor?

The binding of the ligand to the extracellular domain would activate the pathway normally activated by the receptor donating the intracellular domain.

If a cell developed a mutation in its MAP2K1 gene (encodes the MEK protein) that prevented MEK from being recognized by phosphatases, how would the EGFR signaling cascade and the cell’s behavior change?

EGF binding to EGFR initiates a signaling cascade that activates protein kinases through phosphorylation. Active Raf phosphorylates MEK, activating MEK’s kinase activity. If MEK cannot be dephosphorylated, the signaling cascade downstream of MEK will continue to be active after the EGF signal is gone. Therefore, the cell will continue to proliferate and be resistant to cell death (apoptosis).

Glossary


Nerve Impulse: Definition, Propagation and Rate of Conduction

The electro­chemical wave that travels along nerve fibre and stimulates muscles, glands or other nerve cells is called nerve impulse.

Typical structure of neuron:

Neuron is the structural and functional unit of nervous system. It consists of a nerve cell body or soma and two types of processes-axon and dendrite (Fig. 8.29).

It is an irregular-shaped structure in the centre of which there lies a spherical nucleus with prominent nucleolus and Nissl granules. It also contains mitochondria, Golgi body, ribosome and ER etc.

It is the process of the cell body that carries impulse towards the cell body. It is usually short with many branches and contains Nissl granules.

It is the process of a nerve cell body that carries impulse away from it. It is usually single, long slender process and sometimes branched and contains axoplasm, neuro-fibril, etc. It terminates into branches with terminal buttons.

Classification of stimulus:

(a) Subliminal stimulus:

Which can pro­duce the local excitatory state (LES) only?

(b) Threshold value of stimulus:

Which can produce or transform the LES to action potential?

Propagation of Nerve Impulse:

The propagation of nerve impulse involves two major parts – A. Origin/stimu­lation of nerve impulse, B. Propagation/ travelling of nerve impulse.

A. Origin of Nerve impulse:

In resting nerve cells, the surface is posi­tively charged and the interior is negatively charged. When the surface is stimulated the stimulated point becomes negative. The fluids both inside and outside the cell are electro­lytic solution containing 150-160m Eq/litre.

Positive ions and negative ions are accumu­lated along the outer and inner surface of the cell membrane, respectively. This is achieved by Na + outside and K + inside the cell mem­brane, and because Na + is placed above the K + in the electrochemical series.

Development of local excitatory state and Development of action potential:

When stimulation is applied on the nerve cell, external Na + rushes inside the cell making the inner surface positively charged. The amount of Na + is not sufficient to gene­rate action potential and returns to the outside immediately, causing a closed cir­cuit.

Resting potential:

In resting state the nerve fibres remain in polarised state and the membrane potential lies within -70 mv. Na + concentration outside the membrane is higher than that of inside and K + concentration inside the membrane is higher than that of outside. K + can permeate through the membrane at resting condition but the Na + cannot permeate.

State of De-polarisation:

Permeability of Na + to membrane is increased only after stimulation causing de-polarisation. The tremendous increase in Na + conductance during this period is known as activation of membrane. After an initial slow rise, de-po­larisation wave overshoots rapidly and can reach the iso-potential line (above zero line) to approximately +35 mv (Fig. 8.30).

State of re-polarisation:

After reaching the iso-potential line K + begins to come out from inside the membrane, causing outside to be positive again. This is called re-polarisation.

The periodic rise of de-polarisation wave and rapid fall of re-pola­risation wave are known as spike potential.

Negative after potential:

At approxi­mately 2 /3rd of the polarisation, the rate of fall is being abruptly slowed down. This slower fall is known as negative after potential.

Positive after potential:

With the dis­appearance of the negative after potential, although the rising membrane potential is achieved, yet the resting ionic status is not established. It is achieved by the active Na + pump mechanism, which causes the posi­tive after potential. At the same time K + travels back to the inside of the membrane.

B. Propagation/travelling of nerve impulse:

1. Propagation on non-medulated nerve fibre:

According to the membrane theory, nerve impulse is a propagated wave of de-polarisation.

i) When the fibre is excited at a point, the polarity is reversed. This reversed polarity is due to increased permea­bility of Na + to the membrane, which develops de-polarisation wave.

ii) A local circuit current flows between the de-polarised membrane and the resting membrane areas.

iii) Positive current flows inward through the de-polarised membrane and out­ward through the resting membrane and in this way circuit is completed.

iv) The local de-polarisation current then exits the adjacent portion of the mem­brane progressively more and more de-polarisation.

v) The de-polarisation wave travels in all direction along the entire length of the nerve fibre.

2. Propagation in myelinated nerve fibre: Salutatory conduction:

In the myelinated nerve fibre conduction depends upon the similar pattern of circular current flow. Myelin sheath is an effective insulator. Ions cannot pass along the myelin sheaths but nodes of Ranvier permeate ions through it more easily. For this reason the impulse is transmitted from node to node rather than continuously along the entire of the nerve fibre (Fig. 8.32).

The de-polarisation in myelinated action jumps from one node of Ranvier to the next. This jumping or leaping of de-polarisation from node to node is known as saltatory con­duction.

Rate of Conduction of Nerve Impulse:

The basic principle of origin and propagation of nerve impulse is same, both in non-medulated and myelinated nerve fibres but the saltatory mechanism of conduction in myelinated nerve fibre increases the velocity of conduction more than 500 times.

The rate of conduction of a nerve impulse increases with an increase in the cross sectional diame­ter of the neuron and with increasing thick­ness of the myelin sheath. The rate of trans­mission for a given neuron is a constant. Table 8.8 gives an idea about rate of nerve impulse conduction through different nerves of various animals.