Membrane permeability

Cell membranes often consist of a phospholipid bilayer with embedded, integral, and/or
peripheral proteins responsible for communication and transportation of chemicals and ions. An
essential role of biomembranes is to allow movement of all compounds necessary for the normal
function of a cell across the membrane barrier. These compounds include a vast array of
substances like sugars, amino acids, fatty acids, steroids, cations and anions to mention a few.
These compounds must enter or leave the cells in an orderly manner for normal functioning of
the cell. A cell membrane (biomembrane) selectively open to some chemicals and ions but acts
as a barrier to undesired components.
The permeability of a membrane is defined as the rate of passive diffusion of molecules through
the membrane. Permeability depends mainly on the electric charge and polarity of the molecule
and to a lesser extent the molar mass of the molecule.

Types of membrane permeability

 Impermeable
 Semipermeable
 Selectively permeable
 Permeable membrane
An impermeable membrane does not allow any substances to pass through. On the other hand,
a selectively permeable membrane allows only specific solutes pass through while blocking
others. For a permeable membrane, both solutes and solvent molecules are allowed to pass
through. An excellent example of solute and solvent molecules is the passing of both ions and
molecules. Finally, semipermeable membranes are those which only let solvents, such as water,
pass through them.

Selectivity of biomembranes
When a membrane separates two aqueous compartments, some chemicals can move across the
membrane while others cannot. Membrane proteins play a crucial role as transporters of ions and
chemical transfers across the cell membranes. Based on the transport mechanism and
ppermeability, solutes can be divided into three main groups as follows:
 Small lipophilic (lipid soluble) molecules that transfer through the membrane by the sole
diffusion.
 Molecules that cross the membrane with the aid of protein channels.
 Very large molecules that do not cross the membrane at all.

Small Lipophilic Molecules (Passive Diffusion)

Certain substances easily pass through the membrane by passive diffusion. Examples of
chemicals that passively diffuse across the cell membranes are gases, like O 2 and CO2, and small
relatively hydrophobic molecules, such as fatty acids and alcohols. Logarithm of octanol/water
partition coefficient of the solute (Ko/w) can be a measure of lipophilicity (higher the log(Ko/w),
higher the lipophilicity of the solute will be). The solute should also possess enough water
solubility to dissolve in the body fluids. Usually, a compound with log(Ko/w) > 5 is too
hydrophobic to passively diffuse through the biological membranes. In contrast to small
lipophilic molecules, in absence of protein channels, it is difficult for water to pass through the
pure phospholipid membranes via diffusion. Moreover, almost all polar and charged molecules
such as sugars, amino acids, and ions completely fail to cross the pure phospholipid membranes.
Polar and Charged Molecules (Protein-Mediated Transfer)
Biological membranes are permeable not only to gases and small lipophilic molecules (by
passive diffusion processes), but also to many polar and charged molecules, including water, but
through a different path. There are many different proteins located in biomembranes with the
main function of effectively transporting certain solutes across the membrane.
There are two main groups of transport proteins according to their function:
 channel proteins
 carrier proteins.
Channel of proteins promote the transfer of water molecules and certain ions by forming
hydrophilic pores, while carrier proteins bind to specific solutes and carry them across the
membrane. All in all, whether it is of channel or carrier type, protein functions as an enzyme
expediting the transfer of polar and charged molecules. All channel proteins and some carrier
proteins facilitate the transfer of chemical/ions downhill respected to the concentration gradient,
a process known as facilitated diffusion. Facilitated diffusion requires no energy input, in
contrast to active transport processes (solute transport against the concentration gradient) that
require an external source energy.

Large Molecules (Membrane Barriers)

Very large molecules like proteins, polysaccharides or nucleic acids, do not diffuse across the
cell membranes at all. They can pass through the membrane only when broken down into their
component monomers (e.g., amino acids, sugars, or nucleotides).

Factors affecting cell membrane permeability

i. Amount of cholesterol in the membrane: Higher the cholesterol, the lower the
permeability.
ii. Temperature: An increase in temperature increases the permeability, but above 45°C, the
permeability of the membrane decreases.
iii. pH: Increase or decrease in normal pH i.e. 7, decreases the membrane permeability.
iv. Type of molecule: Neutral molecules are easy to pass as compared to charged molecules.

Types of molecules transport channels

There are two types of channels that transport molecules through the cell membrane
i. Channel channels
ii. Ions channels
Water channels
Aquaporins, also called water channels, are channel proteins from a larger family of major
intrinsic proteins that form pores in the membrane of biological cells, mainly facilitating
transport of water between cells. Aquaporins have six membrane-spanning alpha helical domains
with both carboxylic and amino terminals on the cytoplasmic side. Two hydrophobic loops
contain conserved asparagine–proline–alanine ("NPA motif") which form a barrel surrounding a
central pore-like region that contains additional protein density.
Water can pass through the cell membrane through simple diffusion because it is a small
molecule, and through osmosis, in cases where the concentration of water outside of the cell is
greater than that of the inside. However, because water is a polar molecule this process of simple
diffusion is relatively slow, and in tissues with high water permeability the majority of water
passes through aquaporin.
Aquaporins are "the plumbing system for cells". Water moves through cells in an organized way,
most rapidly in tissues that have aquaporin water channels. Aquaporins selectively conduct water
molecules in and out of the cell, while preventing the passage of ions and other solutes. Also
known as water channels, aquaporins are integral membrane pore proteins. Some of them, known
as aquaglyceroporins, also transport other small uncharged dissolved molecules including
ammonia, CO2, glycerol, and urea. However, the water pores completely block ions including
protons, essential to conserve the membrane's electrochemical potential difference. Water
molecules traverse through the pore of the channel in single file. The presence of water channels
increases membrane permeability to water.

Aquaporins

Ion channel
Ion channels are transmembrane channels, pore-like structures composed of proteins. Specific
channels for Na+, K+, Ca++, and Cl– have been identified. Most channels are specific (selective)
for one ion pass across the membrane. The channel pore is typically so small that ions must pass
through it in single file. A channel may have several different states (corresponding to different
conformations of the protein), but each such state is either open or closed. In general, closed
states correspond to a contraction of the pore, making it impassable to the ion. When a channel is
open, ions permeate through the channel pore down the transmembrane concentration gradient
for that particular ion. All ion channels are basically made up of transmembrane subunits that
come together to form a central pore through which ions pass selectively. Channels may have
gates, and are controlled by opening and closing.

Types of ion channels

Ion channels can be classified by how they respond to their environment. For example, channels
can be voltage-sensitive in that they open and close in response to the voltage across the
membrane. Ligand-gated channels form another important class; these ion channels open and
close in response to the binding of a ligand molecule such as a neurotransmitter. Other ion
channels open and close with mechanical forces. Still others, such as those of sensory neurons,
open and close in response to other stimuli, such as light, temperature, or pressure.
The most common types of ion channels are:
i. Leakage Channels
ii. Gated channels
Leakage Channels
Leakage channels are the simplest type of ion channel, in that their permeability is more or less
constant. The types of leakage channels with the greatest significance in neurons are potassium
and chloride channels. Although they are the simplest in theory, most conduct better in one
direction than the other (they are rectifiers) and some are capable of being shut off by ligands
even though they do not require ligands in order to operate.

Gated Channels
There are three main types of gated channels:
i. Chemically-gated or ligand-gated channels,
ii. Voltage-gated channels
iii. Mechanically-gated channels.
iv. Light gated channels

Ligand-gated channels
Ligand-gated ion channels are channels whose permeability is greatly increased when some type
of chemical ligand binds to the protein structure, receptors. They open and close in response to
chemicals, such as neurotransmitters (ex. acetylcholine), hormones, and ions such as H+ and
Ca+2; involved in generating graded potentials. Example: acetylcholine receptor is present in
postsynaptic membrane. It is a complex of five subunits, having a binding site for acetylcholine.
Acetylcholine released from the presynaptic region binds with the binding site of postsynaptic
region, which triggers the opening of the channel and influx of Na+.

Voltage-gated ion channels

Voltage-gated ion channels, also known as voltage-dependent ion channels, are channels whose
permeability is influenced by the membrane potential. They open and close in response to
changes in the voltage or membrane potential; involved in generating action potentials. They
form another very large group, with each member having a particular ion selectivity and a
particular voltage dependence. Many are also time-dependent, in other words, they do not
respond immediately to a voltage change, but only after a delay. Voltage-gated channels are
essential for the generation and propagation of action potentials. Examples include those
selectively permeable to Na+, Ca2+, K+, and Cl- channels.
Mechanically gated channels
Mechanically gated channels - open and close in response to mechanical vibration or pressure,
such as sound waves or the pressure of touch (found in sensory receptors in the skin, ear, etc.);
involved in generating graded potentials.

Light gated channels

Light gated channels - close in response to light (found in the eye); involved in generating graded
potentials.

Cellular connectivity
Animal cells are connected to each other via tight junctions, anchoring junctions, and gap
junctions. On the other hand, plant cells are connected and communicate with each other via
plasmodesmata. Plasmodesmata and gap junctions are more or less the same. However, their
structures are quite different. A tight junction is a watertight seal between two adjacent cells,
while anchoring junctions provide stability and tissue integrity.

Animal cells connectivity

Animal cells can be connected through three forms:
i. Tight junctions
ii. Anchoring junctions
iii. Gap junctions

Tight junction
A tight junction is a watertight seal between two adjacent animal cells. The cells are held tightly
against each other by proteins (predominantly two proteins called claudins and occludins). This
tight adherence prevents materials from leaking between the cells. These junctions are typically
found in epithelial tissues that line internal organs and cavities and comprise most of the skin.
For example, the tight junctions of the epithelial cells lining your urinary bladder prevent urine
from leaking out into the extracellular space.

Tight Junctions: Tight junctions form watertight connections between adjacent animal cells.
Proteins create tight junction adherence.
Anchoring junctions
Anchoring junctions are multiprotein complexes that help cells connect to other cells and the
extracellular matrix. Anchoring junctions are present on the lateral and basal surfaces of cells,
providing strong and flexible connections. Focal adhesions are often formed due to cell
interactions with the extracellular matrix substrata, which initiate signal transduction via kinase
cascades and other mechanisms. Anchoring junctions provide stability and tissue integrity.
There are three types of anchoring junctions:
i. Desmosomes
ii. Hemidesmosomes
iii. Adherens

Desmosomes
Desmosomes appear as dense, symmetrical, disc-shaped plaques on the cell membrane.
Desmosomes act like spot welds between adjacent epithelial cells, connecting them. Short
proteins called cadherins in the plasma membrane connect to intermediate filaments to create
desmosomes.
The cadherins join two adjacent cells together and maintain the cells in a sheet-like formation in
organs and tissues that stretch, such as the skin, heart, and muscles.

Desmosomes: A desmosome forms a very strong spot weld between cells. It is created by the
linkage of cadherins and intermediate filaments.

Hemidesmosomes
Hemidesmosomes look like half a desmosome and link cells to the basal lamina. While similar in
appearance to desmosomes, they include the adhesion proteins called integrins rather than
cadherins. These connections are essential in holding cells together.
Hemidesmosomes

Adherens junctions
Adherens junctions use either cadherins or integrins depending on whether they link to other
cells or the matrix. The junctions are characterized by the presence of the contractile protein
actin located on the cytoplasmic surface of the cell membrane. The actin can connect isolated
patches or form a belt-like structure inside the cell.

Adherens junctions

Gap junctions
Gap junctions are the third type of direct junction found within animal cells. Gap junctions are
channels between adjacent cells that allow for the transport of ions, nutrients, and other
substances that enable cells to communicate. Structurally, however, gap junctions and
plasmodesmata differ although they play the functions. Gap junctions develop when a set of six
proteins (called connexins) in the plasma membrane arrange themselves in an elongated
doughnut-like configuration called a connexon. When the pores (“doughnut holes”) of
connexons in adjacent animal cells align, a channel between the two cells forms. Gap junctions
are particularly important in cardiac muscle. The electrical signal for the muscle to contract is
passed efficiently through gap junctions, which allows the heart muscle cells to contract in
tandem.

Gap junctions

Plasmodesmata
Plasmodesmata are intercellular pores connecting adjacent plant cells allowing membrane and
cytoplasmic continuity and are essential routes for intercellular trafficking, communication and
signaling in plant development and defense. Plasmodesmata (singular is plasmodesma) have two
functions.
 Act as a channel in which molecules can be transported in and out of the plant cells.
 Have a cytoplasmic thread in which communication can transport between cells. Inside of
the plasmodesmata is the plasma membrane, which allows molecules to pass in and out
of the cell.
Plasmodesmata in plant cells are located in the cellular wall. A typical plant cell contains 103 -
105 plasmodesmata. Each plasmodesma is made up of three main layers namely, plasma
membrane, desmotubles, and cytoplasmic sleeve.
The presence of the desmotubule generates a space between the plasma membrane and the
endoplasmic reticulum. Cytoplasmic sleeve is made up of some proteins on the surface of both
membranes to regulate molecule movement.
Plasmodesmata
Cellular communication
There are two kinds of communication in the world of living cells.
i. Communication between cells is called intercellular signaling
ii. Communication within a cell is called intracellular signaling
An easy way to remember the distinction is by understanding that the prefix inter- means
“between” (an interstate highway crosses between states) and intra- means “inside” (an IV means
intravenous or “inside the vein”).
Chemical signals are released by a signaling cell and received by a target cell. Target cells have
proteins called receptors, which bind to signaling molecules and cause a response. Signaling
molecules that bind to receptors are called ligands. Ligands and receptors are specific for each
other; a receptor will typically bind only to its specific ligand.

Forms of signaling
There are four categories of chemical signaling found in multicellular organisms:
i. autocrine signaling
ii. paracrine signaling
iii. endocrine signaling
iv. direct signaling across gap junctions.
The main difference between the different categories of signaling is the distance that the signal
travels to reach the target cell.
In chemical signaling, a cell may target itself, a nearby cell, a distant cell, or a cell that it is
connected to by a gap junction.
Paracrine signaling
Signals that act locally between cells that are close together are called paracrine signals.
Paracrine signals move by diffusion through the extracellular matrix. These types of signals
usually elicit quick responses that last only a short amount of time. In order to keep the response
localized, paracrine ligands are usually quickly degraded by enzymes or removed by neighboring
cells. Removing the signals reestablishes the concentration gradient for the signal molecule,
allowing them to quickly diffuse through the intracellular space if released again.
One example of paracrine signaling is the transfer of signals between nerve cells. The tiny space
between nerve cells where signal transmission occurs is called a synapse. Signals are propagated
along nerve cells by fast-moving electrical impulses. When these impulses reach the end of one
nerve cell, chemical ligands called neurotransmitters are released into the synapse by the
presynaptic cell (the cell emitting the signal). The neurotransmitters diffuse across the synapse.
The small distance between nerve cells allows the signal to travel quickly, which enables an
immediate response, such as, “take your hand off the stove!” When the neurotransmitter binds
the receptor on the surface of the postsynaptic cell, the next electrical impulse is launched. The
neurotransmitters are degraded quickly or are reabsorbed by the presynaptic cell so that the
recipient nerve cell can recover quickly and be prepared to respond rapidly to the next synaptic
signal.
Synapse

Autocrine Signaling
When a cell responds to its own signaling molecule, it is called autocrine signaling (auto =
“self”). Autocrine signaling often occurs during early development of an organism to ensure that
cells develop into the correct tissues. Autocrine signaling also regulates pain sensation and
inflammatory responses. Further, if a cell is infected with a virus, the cell can signal itself to
undergo programmed cell death, killing the virus in the process.

Endocrine Signaling
Signals from distant cells are called endocrine signals, and they originate from endocrine cells.
In the body, many endocrine cells are located in endocrine glands, such as the thyroid gland, the
hypothalamus, and the pituitary gland. These types of signals usually produce a slower response
but have a longer-lasting effect. The ligands released in endocrine signaling are called hormones,
signaling molecules that are produced in one part of the body but affect other body regions some
distance away.
Hormones travel the large distances between endocrine cells and their target cells via the
bloodstream, which is a relatively slow way to move throughout the body. Because of their form
of transport, hormones get diluted and are present in low concentrations when they act on their
target cells. This is different from paracrine signaling, in which local concentrations of signaling
molecules can be very high.

Direct signaling
Gap junctions in animals and plasmodesmata in plants are connections between the plasma
membranes of neighboring cells. These water-filled channels allow small signaling molecules to
diffuse between the two cells. Small molecules, such as calcium ions (Ca 2+), are able to move
between cells, but large molecules like proteins and DNA cannot fit through the channels. The
specificity of the channels ensures that the cells remain independent but can quickly and easily
transmit signals. Direct signaling allows a group of cells to coordinate their response to a signal
that only one of them may have received. In plants, plasmodesmata are ubiquitous, making the
entire plant into a giant communication network.

Receptors
Receptors are protein molecules in the target cell or on its surface that bind to ligands.

Types of Receptors
There are two types of receptors:
i. Internal receptors
ii. Cell-surface receptors.

Internal receptors
Internal receptors, also known as intracellular or cytoplasmic receptors, are found in the
cytoplasm of target cells and respond to hydrophobic ligand molecules that are able to travel
across the plasma membrane. Once inside the cell, many of these molecules bind to proteins that
act as regulators of mRNA synthesis (transcription) to mediate gene expression. Gene expression
is the cellular process of transforming the information in a cell’s DNA into a sequence of amino
acids, which ultimately forms a protein. When the ligand binds to the internal receptor, a
conformational change is triggered that exposes a DNA-binding site on the receptor protein. The
ligand-receptor complex moves into the nucleus, then binds to specific regulatory regions of the
chromosomal DNA and promotes the initiation of transcription. Transcription is the process of
copying the information in a cell’s DNA into a special form of RNA called messenger RNA
(mRNA); the cell uses information in the mRNA to link specific amino acids in the correct order,
producing a protein. Thus, when a ligand binds to an internal receptor, it can directly influence
gene expression in the target cell.
Hydrophobic signaling molecules typically diffuse across the plasma membrane and interact with
intracellular receptors in the cytoplasm. Many intracellular receptors are transcription factors that
interact with DNA in the nucleus and regulate gene expression.

Cell-Surface Receptors
Cell-surface receptors, also known as transmembrane receptors, are integral proteins that bind to
external signaling molecules. These receptors span the plasma membrane and perform signal
transduction, in which an extracellular signal is converted into an intercellular signal. Signal
transduction is a process where cells translate signals from the extracellular environment into
changes inside the cell. Because cell-surface receptor proteins are fundamental to normal cell
functioning, it should come as no surprise that a malfunction in any one of these proteins could
have severe consequences. Errors in the protein structures of certain receptor molecules have
been shown to play a role in hypertension (high blood pressure), asthma, heart disease, and
cancer.

Each cell-surface receptor has three main components:

i. an external ligand-binding domain, or extracellular domain
ii. a hydrophobic membrane-spanning region
iii. an intracellular domain.

Categories of cell surface receptors

Cell-surface receptors are involved in most of the signaling in multicellular organisms. There are
three general categories of cell-surface receptors:
i. enzyme-linked receptors
ii. ion channel-linked receptors
iii. G-protein-linked receptors.
Hydrophilic signaling molecules typically work by binding to the extracellular portion of a
receptor protein. The signal is then transduced across the membrane.

Enzyme-linked receptors
Enzyme-linked receptors are cell-surface receptors with intracellular domains that are associated
with an enzyme. In some cases, the intracellular domain of the receptor itself is an enzyme.
Other enzyme-linked receptors have a small intracellular domain that interacts directly with an
enzyme.
Enzyme-linked receptors normally have large extracellular and intracellular domains, but the
membrane-spanning region consists of a single alpha-helix in the peptide strand. When a ligand
binds to the extracellular domain of an enzyme-linked receptor, a signal is transferred through
the membrane, activating the enzyme. Activation of the enzyme sets off a chain of events within
the cell that eventually leads to a response.
A receptor tyrosine kinase is an enzyme-linked receptor with a single transmembrane region, and
extracellular and intracellular domains. Binding of a signaling molecule to the extracellular
domain causes the receptor to dimerize. Tyrosine residues on the intracellular domain are then
auto-phosphorylated, triggering a downstream cellular response. The signal is terminated by a
phosphatase that removes the phosphates from the phosphotyrosine residues.
Enzyme-linked receptor, a receptor tyrosine kinase

Ion channel-linked receptors

Ion channel-linked receptors bind to a ligand and open a channel through the membrane that
allows specific ions to pass through. This type of cell-surface receptor has an extensive
membrane-spanning region with hydrophobic amino acids. Conversely, the amino acids that line
the inside of the channel are hydrophilic to allow for the passage of ions. When a ligand binds to
the extracellular region of the channel, there is a conformational change in the protein’s structure
that allows ions such as sodium, calcium, magnesium, or hydrogen to pass through.

Ion channel-linked receptors

G-protein-linked receptors
G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act
as molecular switches inside cells, and are involved in transmitting signals from a variety of
stimuli outside a cell to its interior. Their activity is regulated by factors that control their ability
to bind to and hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP). When
they are bound to GTP, they are 'on', and, when they are bound to GDP, they are 'off'. G proteins
belong to the larger group of enzymes called GTPases. Some G proteins, such as the signaling
protein Ras, are small proteins with a single subunit. G-protein-coupled receptors (GPCRs) are
the largest and most diverse group of membrane receptors in eukaryotes. G-protein-linked
receptors bind to a ligand and activate an associated G-protein. The activated G- protein then
interacts with a nearby membrane protein, which may be an ion channel or an enzyme. All G-
protein-linked receptors have seven transmembrane domains, but each receptor has a specific
extracellular domain and G-protein-binding site. G-protein linked receptors are used in many
physiological processes including those for vision transduction, taste, and regulation of immune
system and inflammation.
Cell signaling using G-protein-linked receptors occurs as a cycle. Once the ligand binds to the
receptor, the resultant shape change activates the G-protein, which releases GDP and picks up
GTP. The subunits of the G-protein then split into α and βγ subunits. One or both of these G-
protein fragments may be able to activate other proteins in the cell. After a while, the GTP on the
active α subunit of the G-protein is hydrolyzed to GDP and the βγ subunit is deactivated. The
subunits re-associate to form the inactive G-protein and the cycle begins again.
Signaling Molecules
Produced by signaling cells, ligands are chemical signals that travel to target cells and cause a
response. The types of molecules that serve as ligands are incredibly varied and range from small
proteins to small ions. Ligands are categorized as either small hydrophobic ligands, which can
cross plasma membranes, or water-soluble ligands, which cannot.
Small Hydrophobic Ligands
Small hydrophobic ligands, also called lipid-soluble ligands, can directly diffuse through the
plasma membrane and interact with internal receptors. Important members of this class of
ligands are the steroid hormones. Steroids are lipids that have a hydrocarbon skeleton with four
fused rings; different steroids have different functional groups attached to the carbon skeleton.
Steroid hormones include the female sex hormone estradiol, which is a type of estrogen; the male
sex hormone testosterone; and cholesterol, which is an important structural component of
biological membranes and a precursor of steroid hormones (Figure 9.10). Other hydrophobic
hormones include thyroid hormones and vitamin D. In order to be soluble in blood, hydrophobic
ligands must bind to carrier proteins while they are being transported through the bloodstream.
G- protein receptor.

Water-Soluble Ligands
Since water-soluble ligands are polar, they cannot pass through the plasma membrane unaided.
Sometimes they are too large to pass through the membrane at all. Instead, most water-soluble
ligands bind to the extracellular domain of cell-surface receptors (see Figure 9.5). This group of
ligands is quite diverse and includes small molecules, peptides, and proteins.

Propagation of the Signal

Once a water-soluble ligand binds to its 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 since internal receptors are able to
enter the cell.
When a ligand binds to its receptor, conformational changes occur that affect the receptor’s
intracellular domain. These conformational changes 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.

Signaling Pathways and Signal Amplification

Although signaling molecules are often found at very low concentrations, they may produce
profound effects. 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/or activated
proteins activate other proteins or messengers. Each member of the pathway can activate
thousands of the next member of the pathway in a process called signal amplification. Since the
signal is amplified at each step, a very large response can be generated from a single receptor
binding a ligand.
An example of a signaling pathway is shown is epidermal growth factor (EGF) is a signaling
molecule that is involved in the regulation of cell growth, wound healing, and tissue repair. The
receptor for EGF (EGFR) is a tyrosine kinase. An activated kinase phosphorylates and activates
many downstream molecules. When EGF binds to EGFR, a cascade of downstream
phosphorylation events signals the cell to grow and divide. If EGFR is activated at inappropriate
times, uncontrolled cell growth (cancer) may occur.

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 to activate the next
component of the pathway. The following are some of the more common events in intracellular
signaling phosphorylation and second message.

Phosphorylation
One of the most common chemical modifications that occurs in signaling pathways is the
addition of a phosphate group to a molecule in a process called phosphorylation. The phosphate
can be added to a nucleotide. 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. ATP is often used as the substrate to add
the phosphate group to this amino acid. The phosphate group often results in a shape change in
the protein that can activate or turns off the function of the protein. Phosphorylation may activate
or inactivate enzymes, and the reversal of phosphorylation, dephosphorylation, 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. A second messenger
utilized by many different cell types is cyclic adenosine monophosphate (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, and the target
proteins in each kind of cell are different. Another secondary messenger is Ca 2+which can be
released to flood the cell.

Response to the Signal

Using signal transduction pathways, receptors in the plasma membrane produce a variety of
effects on the cell. Inside the cell, ligands bind to their internal receptors, allowing them to
directly affect the cell’s DNA and protein-producing machinery. The results of signaling
pathways are extremely varied and depend on the type of cell involved as well as the external
and internal conditions

Responses to the Signaling Pathway

i. Gene expression: Some signal transduction pathways regulate the transcription of RNA.
Others regulate the translation of proteins.
 ii. Increase in cellular metabolism: The activation of β-adrenergic receptors in muscle cells
by adrenaline leads to an increase in cyclic AMP inside the cell. Adrenaline is a hormone
produced by the adrenal gland that readies the body for short-term emergencies.
iii. Cell growth: Cells do not normally divide unless they are stimulated by signals from
other cells. The ligands that promote cell growth are called growth factors. Most growth
factors bind to cell-surface receptors that are linked to tyrosine kinases.
iv. Cell death: When a cell is damaged, 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.

Termination of Signaling Pathways

One method of stopping a specific signal is to degrade the ligand or remove it so that it can no
longer access its receptor. One reason that hydrophobic hormones like estrogen and testosterone
trigger long-lasting events is because they bind to carrier proteins. These proteins allow the
insoluble molecules to be soluble in blood, but they also protect the hormones from degradation
by circulating enzymes.
Inside the cell, many different enzymes reverse the cellular modifications that result from
signaling cascades. For example, phosphatases are enzymes that remove the phosphate group
attached to proteins by kinases in a process called dephosphorylation. cAMP is degraded into
AMP by phosphodiesterase, thereby terminating its signal. Similarly, the release of calcium
stores is reversed by Ca2+ pumps that are located in cell membranes.