Overview of Cell Communication

Skills to Develop
 Describe four types of signaling found in multicellular organisms
 Compare internal receptors with cell-surface receptors
 Recognize the relationship between a ligand’s structure and its mechanism of action

There are two kinds of communication in the world of living cells. Communication between cells
is called intercellular signaling, and communication within a cell is called intracellular signaling.
An easy way to remember the distinction is by understanding the Latin origin of the prefixes:
inter- means "between" (for example, intersecting lines are those that cross each other) and intra-
means "inside" (like intravenous).

Chemical signals are released by signaling cells in the form of small, usually volatile or soluble
molecules called ligands. A ligand is a molecule that binds another specific molecule, in some
cases, delivering a signal in the process. Ligands can thus be thought of as signaling molecules.
Ligands interact with proteins in target cells, which are cells that are affected by chemical
signals; these proteins are also called receptors. Ligands and receptors exist in several varieties;
however, a specific ligand will have a specific receptor that typically binds only that ligand.

Forms of Signaling

There are four categories of chemical signaling found in multicellular organisms: paracrine
signaling, endocrine signaling, autocrine signaling, and direct signaling across gap junctions.
The main difference between the different categories of signaling is the distance that the signal
travels through the organism to reach the target cell. Not all cells are affected by the same
signals.
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 ligand molecules are normally quickly degraded by enzymes or removed by
neighboring cells. Removing the signals will reestablish the concentration gradient for the signal,
allowing them to quickly diffuse through the intracellular space if released again.

Paracrine signaling is a form of cell communication where signaling molecules, often called
ligands, are released by a cell and act on neighboring cells within a localized area. Unlike
endocrine signaling, where hormones are released into the bloodstream to affect distant targets,
paracrine signaling involves direct interaction between cells that are close to each other, usually
within the same tissue.

Blood clotting is another example of paracrine signaling. Broken endothelial tissue releases
signaling molecules such as thromboxane A2 into the affected tissue.

Key Features of Paracrine Signaling:

1. Local Signaling: The signaling molecules diffuse through the extracellular fluid to
nearby target cells, affecting their behavior.
2. Short-Distance Action: Paracrine signals generally act over short distances, influencing
cells in the immediate vicinity of the signaling cell.
3. Molecules Involved: Common signaling molecules in paracrine signaling include growth
factors, cytokines, and prostaglandins.
4. Cell Types: Paracrine signaling often occurs between various types of cells within
tissues. For example, neurons can release neurotransmitters to communicate with
neighboring cells or immune cells can release cytokines to modulate the behavior of
surrounding cells.
5. Examples in the Body:
o Neurotransmitter Release: In the nervous system, neurotransmitters released by
one neuron can affect neighboring neurons or muscle cells.
o Growth Factors: In wound healing, growth factors released by one cell can
stimulate nearby cells to proliferate and repair tissue.

Mechanism:

1. Secretion: The signaling cell releases ligands (signaling molecules) into the extracellular
space.
2. Diffusion: These molecules diffuse through the extracellular matrix.
3. Binding to Receptors: Target cells nearby have specific receptors that bind to these
signaling molecules, leading to a cascade of intracellular events.
4. Response: The target cell undergoes a physiological response, which may include
changes in gene expression, cell division, or secretion.

Paracrine signaling is critical for processes like tissue development, immune responses, and
inflammation.
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 ligands
can be very high.

Endocrine signaling is a type of long-distance cell communication where signaling molecules,

known as hormones, are secreted by endocrine glands or cells into the bloodstream. These
hormones travel through the circulatory system to target cells located far from the site of
secretion. This form of signaling is essential for regulating diverse physiological processes,
including growth, metabolism, reproduction, and homeostasis.

Key Features of Endocrine Signaling

1. Long-Distance Communication: Hormones act on target cells that may be located far
away from the secreting cells.
2. Bloodstream Transport: Hormones are released into the bloodstream, ensuring their
delivery to distant tissues.
3. Specificity: Target cells must express specific receptors for the hormone to elicit a
response.
4. Slower Onset, Longer Duration: Compared to other signaling mechanisms like
paracrine or synaptic signaling, endocrine signaling often has a slower onset but longer-
lasting effects.
5. Regulatory Role: This type of signaling regulates critical systemic processes, including:
o Growth and development
o Energy metabolism
o Reproduction
o Stress response

Mechanism of Endocrine Signaling

1. Hormone Synthesis: Endocrine glands synthesize hormones in response to specific

stimuli (e.g., stress, changes in nutrient levels, or feedback mechanisms).
2. Secretion: Hormones are released into the bloodstream or lymphatic system.
3. Transport: Hormones circulate in the blood, sometimes bound to carrier proteins for
protection and extended half-life.
 4. Receptor Binding: Target cells with specific receptors bind the hormone. The receptor
can be located:
o On the cell surface (for peptide/protein hormones like insulin).
o Inside the cell (for lipid-soluble hormones like steroids or thyroid hormones).
5. Cellular Response: Binding triggers intracellular signaling pathways, leading to
physiological effects such as changes in gene expression, metabolism, or ion channel
activity.

Examples of Endocrine Glands and Hormones

1. Pituitary Gland:
o Hormones: Growth hormone (GH), Adrenocorticotropic hormone (ACTH),
Prolactin
o Function: Growth, stress response, milk production
2. Thyroid Gland:
o Hormones: Thyroxine (T4), Triiodothyronine (T3)
o Function: Regulates metabolism and energy levels
3. Adrenal Glands:
o Hormones: Cortisol, Epinephrine
o Function: Stress response, regulation of blood sugar
4. Pancreas:
o Hormones: Insulin, Glucagon
o Function: Blood glucose regulation
5. Gonads (Ovaries/Testes):
o Hormones: Estrogen, Testosterone
o Function: Reproductive function, secondary sexual characteristics

Autocrine Signaling

Autocrine signals are produced by signaling cells that can also bind to the ligand that is released.
This means the signaling cell and the target cell can be the same or a similar cell (the
prefix auto- means self, a reminder that the signaling cell sends a signal to itself). This type of
signaling often occurs during the early development of an organism to ensure that cells develop
into the correct tissues and take on the proper function. 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. In some cases,
neighboring cells of the same type are also influenced by the released ligand. In embryological
development, this process of stimulating a group of neighboring cells may help to direct the
differentiation of identical cells into the same cell type, thus ensuring the proper developmental
outcome.

Autocrine signaling is a form of cell communication in which a cell releases signaling

molecules that bind to receptors on its own surface, leading to a response in the same cell. This
type of signaling is essential for processes like cell growth, differentiation, immune responses,
and feedback regulation.

Key Features of Autocrine Signaling

1. Self-Targeting: The signaling cell and the target cell are the same.
2. Local and Self-Contained: The signaling molecules act within the vicinity of the cell
that secretes them.
3. Feedback Regulation: Autocrine signaling often functions as a feedback mechanism to
regulate processes like cell proliferation or apoptosis.
4. Specificity: The cell must have receptors that recognize and respond to its own signaling
molecules.

Mechanism of Autocrine Signaling

1. Signal Production: The cell synthesizes and releases signaling molecules (e.g., growth
factors, cytokines).
2. Receptor Binding: The signaling molecules bind to receptors on the surface of the same
cell or receptors inside the cell.
3. Signal Transduction: Binding triggers a cascade of intracellular signaling pathways,
leading to a response.
4. Response: The cell undergoes a physiological change, such as altered gene expression,
proliferation, or secretion.

Examples of Autocrine Signaling

1. Immune System:
o T-Cells: Activated T-cells secrete interleukin-2 (IL-2), which binds to their own
receptors to stimulate their proliferation and activity.
2. Cancer Cells:
o Many cancer cells utilize autocrine signaling to sustain their growth and evade
normal regulatory mechanisms. For example, tumor cells often produce growth
factors that stimulate their own proliferation.
3. Stem Cells:
 o Autocrine signaling helps maintain stem cell renewal and differentiation.

Functions of Autocrine Signaling

 Growth Regulation: Helps cells regulate their own division and proliferation.
 Immune Response: Activates or modulates immune cells during infections or
inflammation.
 Wound Healing: Promotes cell migration and proliferation in response to injury.
 Cancer Progression: Plays a role in uncontrolled cell growth and survival in cancer.

Direct Signaling Across Gap Junctions

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,
called intracellular mediators, to diffuse between the two cells. Small molecules, such as calcium
ions (Ca2+), 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. The transfer of signaling molecules communicates
the current state of the cell that is directly next to the target cell; this 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.

Direct signaling across gap junctions is a form of cell communication where adjacent cells
exchange ions, molecules, and electrical signals directly through specialized structures called
gap junctions. This form of signaling does not rely on extracellular signaling molecules, as the
exchange occurs via channels that physically connect the cytoplasm of neighboring cells.

Key Features of Gap Junction Signaling

1. Direct Cytoplasmic Connection:

o Gap junctions form conduits that allow direct communication between the
cytoplasm of two adjacent cells.
o These channels are made of protein complexes called connexons, which are
composed of subunits called connexins.
2. Selective Transfer:
o Small molecules (e.g., ions, second messengers like calcium and cyclic AMP) and
electrical signals can pass through gap junctions.
 o Larger molecules, such as proteins and nucleic acids, cannot pass through.
3. Bidirectional Communication:
o Gap junctions typically allow substances to move in both directions, enabling
reciprocal signaling.
4. Rapid Signal Transmission:
o Communication via gap junctions is instantaneous, making it ideal for
synchronized cellular activities.

Mechanism of Signaling

1. Formation of Connexons:
o Each cell contributes half of the gap junction channel, called a hemichannel or
connexon.
o Two connexons align and dock to form a continuous channel between the cells.
2. Transfer of Signals:
o Small ions (e.g., Na⁺, K⁺, Ca²⁺) and signaling molecules diffuse through the gap
junctions.
o Electrical signals can propagate directly, enabling fast communication.
3. Regulation:
o Gap junctions can open or close in response to changes in cellular conditions,
such as pH, calcium levels, or membrane potential.

Examples of Direct Signaling Across Gap Junctions

1. Cardiac Muscle Cells:

o Gap junctions in intercalated discs connect cardiac muscle cells, allowing the
rapid spread of electrical signals (action potentials) that synchronize heart
contractions.
o This ensures efficient and coordinated pumping of blood.
2. Neurons:
o In some regions of the nervous system, electrical synapses use gap junctions for
direct transmission of electrical signals, enabling rapid and synchronized neuronal
firing.
3. Smooth Muscle Cells:
o Gap junctions allow ion flow between smooth muscle cells, coordinating
contraction in organs like the intestines and blood vessels.
4. Developmental Processes:
o During embryonic development, gap junctions enable direct communication
between cells to coordinate growth and differentiation.
5. Metabolic Coupling:
o In tissues like the liver, gap junctions facilitate the transfer of metabolites (e.g.,
glucose or ATP) between cells to maintain metabolic balance.
Advantages of Gap Junction Signaling

 Speed: Communication is almost instantaneous, ideal for rapid responses.

 Coordination: Synchronizes the activity of cell groups (e.g., cardiac muscle, neurons).
 Energy Efficiency: Does not require extracellular signaling molecules or receptors.

Clinical Implications

 Heart Disease: Malfunction of gap junctions can lead to arrhythmias by disrupting the
synchronization of cardiac muscle cells.
 Cancer: Altered gap junction communication is often seen in cancerous tissues,
contributing to uncontrolled cell growth.
 Neurological Disorders: Impaired gap junction function is associated with conditions
like epilepsy and neurodegeneration.

Gap junction signaling is fundamental for maintaining the coordinated activity of many tissues
and organs in the body.

Comparison of Signaling Types

Feature Endocrine Paracrine Autocrine Synaptic

Long (via Very short
Distance Short (local area) Self-targeted
bloodstream) (synapse)
Speed Slow Moderate Moderate Fast
Duration Long-lasting Short to moderate Short Short
Growth factors, Immune signaling
Examples Insulin, Cortisol Neurotransmitters
Cytokines molecules

Endocrine signaling is critical for maintaining the body's internal balance and responding to
environmental changes.
Types of Receptors

Receptors are specialized proteins that recognize and bind specific signaling molecules (ligands)
such as hormones, neurotransmitters, or growth factors. Once activated, receptors initiate a
cellular response. Receptors can be classified based on their location and mechanism of action.
Below are the major types of receptors:

1. Intracellular Receptors

 Location: Found inside the cell, either in the cytoplasm or nucleus.

 Ligand Type: Bind to hydrophobic (lipid-soluble) molecules that can cross the cell
membrane, such as steroid hormones and thyroid hormones.
 Mechanism:
o Ligand enters the cell and binds to the intracellular receptor.
o The receptor-ligand complex acts as a transcription factor, directly affecting gene
expression.
 Examples:
o Glucocorticoid receptor: Binds cortisol to regulate stress responses.
o Estrogen receptor: Regulates gene expression related to reproductive functions.
 Key Functions: Regulate gene transcription, often leading to slower but long-lasting
effects.

2. Cell Surface Receptors

These receptors are embedded in the plasma membrane and are involved in signal transduction.
They bind hydrophilic ligands that cannot cross the cell membrane.

a. Ion Channel-Linked Receptors (Ligand-Gated Ion Channels)

 Function: Open or close ion channels in response to ligand binding, altering ion flow
across the membrane.
 Examples:
o Nicotinic acetylcholine receptor: Opens ion channels for Na⁺ and K⁺ upon
acetylcholine binding, crucial for muscle contraction.
o GABA receptors: Allow Cl⁻ ion flow, leading to inhibitory signaling in neurons.
 Key Role: Rapid signaling, especially in the nervous system.

b. G Protein-Coupled Receptors (GPCRs)

 Structure: Seven transmembrane domains coupled with intracellular G proteins.

 Mechanism:
 o Ligand binding activates the G protein.
o The G protein triggers intracellular signaling cascades involving second
messengers (e.g., cyclic AMP, Ca²⁺).
 Examples:
o Beta-adrenergic receptors: Bind adrenaline to regulate heart rate and energy
metabolism.
o Rhodopsin: A GPCR involved in vision.
 Key Role: Regulate diverse processes like sensory perception, metabolism, and immune
responses.

c. Enzyme-Linked Receptors

 Structure: Contain an extracellular ligand-binding domain and an intracellular enzyme

domain.
 Mechanism:
o Ligand binding activates the enzymatic domain (e.g., tyrosine kinase activity).
o This activation triggers intracellular signaling cascades.
 Examples:
o Insulin receptor: Activates signaling pathways for glucose uptake.
o Epidermal growth factor receptor (EGFR): Promotes cell proliferation and
survival.
 Key Role: Cell growth, differentiation, and metabolism.

d. Cytokine Receptors

 Mechanism:
o Often associated with intracellular kinases (e.g., JAK-STAT pathway).
o Ligand binding activates the kinases, leading to transcriptional changes.
 Examples:
o Interleukin receptors: Regulate immune responses.
o Erythropoietin receptor: Stimulates red blood cell production.

3. Sensory Receptors

Specialized receptors in sensory systems that detect environmental stimuli.

a. Mechanoreceptors

 Respond to mechanical stimuli like pressure, vibration, and stretch.

 Examples:
o Pacinian corpuscles (pressure detection in the skin).
o Hair cells in the cochlea (sound detection).

b. Photoreceptors
  Detect light in the retina of the eye.
 Examples:
o Rods (low-light vision).
o Cones (color vision).

c. Chemoreceptors

 Detect chemical stimuli such as taste and smell.

 Examples:
o Olfactory receptors (smell).
o Taste receptors (sweet, salty, bitter, sour, umami).

d. Thermoreceptors

 Detect temperature changes.

 Examples:
o TRP channels in skin neurons (hot or cold detection).

e. Nociceptors

 Detect pain stimuli, including mechanical, thermal, and chemical damage.

4. Pattern Recognition Receptors (PRRs)

 Function: Detect pathogen-associated molecular patterns (PAMPs) and danger-

associated molecular patterns (DAMPs) during immune responses.
 Examples:
o Toll-like receptors (TLRs): Recognize bacterial and viral components.
o NOD-like receptors (NLRs): Detect intracellular pathogens.
 Key Role: Activate innate immune responses.

Comparison Table of Receptor Types

Response
Receptor Type Location Ligand Examples Examples
Time
Intracellular Cytoplasm or Steroid hormones,
Hours to days Glucocorticoid receptor
Receptors nucleus T3/T4
Ion Channel- Cell Ions, Nicotinic acetylcholine
Milliseconds
Linked membrane neurotransmitters receptor
Cell Hormones, Seconds to Beta-adrenergic
GPCRs
membrane neurotransmitters minutes receptor
 Response
Receptor Type Location Ligand Examples Examples
Time
Cell Insulin, growth Minutes to
Enzyme-Linked Insulin receptor, EGFR
membrane factors hours
Sensory Sensory Environmental Photoreceptors,
Variable
Receptors organs stimuli mechanoreceptors
Minutes to
PRRs Immune cells Pathogen components Toll-like receptors
hours

Key Insights

 Different receptors are specialized for distinct types of signals and response speeds.
 Proper receptor function is essential for maintaining homeostasis and responding to
environmental changes.
 Dysregulation of receptors is linked to diseases such as cancer, diabetes, and
neurodegenerative disorders.

Receptors are protein molecules in the target cell or on its surface that bind ligand. There are two
types of receptors, internal receptors and cell-surface receptors.

Internal receptors

Internal receptors, also known as intracellular or cytoplasmic receptors, are found in the
cytoplasm of the cell 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 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 (which moves out into the cytoplasm and
associates with ribosomes) to link specific amino acids in the correct order, producing a protein.
Internal receptors can directly influence gene expression without having to pass the signal on to
other receptors or messengers.

Cell-Surface Receptors

Cell-surface receptors, also known as transmembrane receptors, are cell surface, membrane-
anchored (integral) proteins that bind to external ligand molecules. This type of receptor spans
the plasma membrane and performs signal transduction, in which an extracellular signal is
converted into an intercellular signal. Ligands that interact with cell-surface receptors do not
have to enter the cell that they affect. Cell-surface receptors are also called cell-specific proteins
or markers because they are specific to individual cell types.

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: an external ligand-binding domain, a
hydrophobic membrane-spanning region, and an intracellular domain inside the cell. The ligand-
binding domain is also called the extracellular domain. The size and extent of each of these
domains vary widely, depending on the type of receptor.

Evolution Connection: How Viruses Recognize a Host

Unlike living cells, many viruses do not have a plasma membrane or any of the structures
necessary to sustain life. Some viruses are simply composed of an inert protein shell containing
DNA or RNA. To reproduce, viruses must invade a living cell, which serves as a host, and then
take over the hosts cellular apparatus. But how does a virus recognize its host?

Viruses often bind to cell-surface receptors on the host cell. For example, the virus that causes
human influenza (flu) binds specifically to receptors on membranes of cells of the respiratory
system. Chemical differences in the cell-surface receptors among hosts mean that a virus that
infects a specific species (for example, humans) cannot infect another species (for example,
chickens).

However, viruses have very small amounts of DNA or RNA compared to humans, and, as a
result, viral reproduction can occur rapidly. Viral reproduction invariably produces errors that
can lead to changes in newly produced viruses; these changes mean that the viral proteins that
interact with cell-surface receptors may evolve in such a way that they can bind to receptors in a
new host. Such changes happen randomly and quite often in the reproductive cycle of a virus, but
the changes only matter if a virus with new binding properties comes into contact with a suitable
host. In the case of influenza, this situation can occur in settings where animals and people are in
close contact, such as poultry and swine farms. 1 Once a virus jumps to a new host, it can spread
quickly. Scientists watch newly appearing viruses (called emerging viruses) closely in the hope
that such monitoring can reduce the likelihood of global viral epidemics.

Cell-surface receptors are involved in most of the signaling in multicellular organisms. There are
three general categories of cell-surface receptors: ion channel-linked receptors, G-protein-linked
receptors, and enzyme-linked receptors.

Ion channel-linked receptors bind a ligand and open a channel through the membrane that allows
specific ions to pass through. To form a channel, this type of cell-surface receptor has an
extensive membrane-spanning region. In order to interact with the phospholipid fatty acid tails
that form the center of the plasma membrane, many of the amino acids in the membrane-
spanning region are hydrophobic in nature. Conversely, the amino acids that line the inside of the
channel are hydrophilic to allow for the passage of water or ions. When a ligand binds to the
extracellular region of the channel, there is a conformational change in the proteins structure that
allows ions such as sodium, calcium, magnesium, and hydrogen to pass through

G-protein-linked receptors bind a ligand and activate a membrane protein called a G-protein. The
activated G-protein then interacts with either an ion channel or an enzyme in the membrane. All
G-protein-linked receptors have seven transmembrane domains, but each receptor has its own
specific extracellular domain and G-protein-binding site.

Cell signaling using G-protein-linked receptors occurs as a cyclic series of events. Before the
ligand binds, the inactive G-protein can bind to a newly revealed site on the receptor specific for
its binding. Once the G-protein 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
the α subunit and the βγ subunit. One or both of these G-protein fragments may be able to
activate other proteins as a result. 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 reassociate to form the
inactive G-protein, and the cycle begins anew.
Heterotrimeric G proteins have three subunits: α, β, and γ. When a signaling molecule binds to a
G-protein-coupled receptor in the plasma membrane, a GDP molecule associated with
the α subunit is exchanged for GTP. The β and γ subunits dissociate from the α subunit, and a
cellular response is triggered either by the α subunit or the dissociated βγ pair. Hydrolysis of
GTP to GDP terminates the signal.
G-protein-linked receptors have been extensively studied and much has been learned about their
roles in maintaining health. Bacteria that are pathogenic to humans can release poisons that
interrupt specific G-protein-linked receptor function, leading to illnesses such as pertussis,
botulism, and cholera. In cholera, for example, the water-borne bacterium Vibrio
cholerae produces a toxin, choleragen, that binds to cells lining the small intestine. The toxin
then enters these intestinal cells, where it modifies a G-protein that controls the opening of a
chloride channel and causes it to remain continuously active, resulting in large losses of fluids
from the body and potentially fatal dehydration as a result.
Transmitted primarily through contaminated drinking water, cholera is a major cause of death in
the developing world and in areas where natural disasters interrupt the availability of clean
water. The cholera bacterium, Vibrio cholerae, creates a toxin that modifies G-protein-mediated
cell signaling pathways in the intestines. Modern sanitation eliminates the threat of cholera
outbreaks, such as the one that swept through New York City in 1866. This poster from that era
shows how, at that time, the way that the disease was transmitted was not understood. (credit:
New York City Sanitary Commission)

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. The enzyme-linked receptors normally have large extracellular and intracellular
domains, but the membrane-spanning region consists of a single alpha-helical region of the
peptide strand. When a ligand binds to the extracellular domain, 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. One example of this type of enzyme-linked receptor
is the tyrosine kinase receptor. A kinase is an enzyme that transfers phosphate groups from ATP
to another protein. The tyrosine kinase receptor transfers phosphate groups to tyrosine molecules
(tyrosine residues). First, signaling molecules bind to the extracellular domain of two nearby
tyrosine kinase receptors. The two neighboring receptors then bond together or dimerize.
Phosphates are then added to tyrosine residues on the intracellular domain of the receptors
(phosphorylation). The phosphorylated residues can then transmit the signal to the next
messenger within the cytoplasm.
Figure 9.1.79.1.7: 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 autophosphorylated, triggering a downstream cellular response. The
signal is terminated by a phosphatase that removes the phosphates from the phosphotyrosine
residues.

HER2 is a receptor tyrosine kinase. In 30 percent of human breast cancers, HER2 is permanently
activated, resulting in unregulated cell division. Lapatinib, a drug used to treat breast cancer,
inhibits HER2 receptor tyrosine kinase autophosphorylation (the process by which the receptor
adds phosphates onto itself), thus reducing tumor growth by 50 percent. Besides
autophosphorylation, which of the following steps would be inhibited by Lapatinib?

A. Signaling molecule binding, dimerization, and the downstream cellular response

B. Dimerization, and the downstream cellular response
C. The downstream cellular response
D. Phosphatase activity, dimerization, and the downstream cellular response

Signaling Molecules

Produced by signaling cells and the subsequent binding to receptors in target cells, ligands act as
chemical signals that travel to the target cells to coordinate responses. The types of molecules
that serve as ligands are incredibly varied and range from small proteins to small ions like
calcium (Ca2+).

Small Hydrophobic Ligands

Small hydrophobic 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 9.1.89.1.8). 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.

Figure 9.1.89.1.8: Steroid hormones have similar chemical structures to their precursor,
cholesterol. Because these molecules are small and hydrophobic, they can diffuse directly across
the plasma membrane into the cell, where they interact with internal receptors.

Water-Soluble Ligands

Water-soluble ligands are polar and therefore 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. This group of ligands is
quite diverse and includes small molecules, peptides, and proteins.

Other Ligands

Nitric oxide (NO) is a gas that also acts as a ligand. It is able to diffuse directly across the plasma
membrane, and one of its roles is to interact with receptors in smooth muscle and induce
relaxation of the tissue. NO has a very short half-life and therefore only functions over short
distances. Nitroglycerin, a treatment for heart disease, acts by triggering the release of NO,
which causes blood vessels to dilate (expand), thus restoring blood flow to the heart. NO has
become better known recently because the pathway that it affects is targeted by prescription
medications for erectile dysfunction, such as Viagra (erection involves dilated blood vessels).

Summary
Cells communicate by both inter- and intracellular signaling. Signaling cells secrete ligands that
bind to target cells and initiate a chain of events within the target cell. The four categories of
signaling in multicellular organisms are paracrine signaling, endocrine signaling, autocrine
signaling, and direct signaling across gap junctions. Paracrine signaling takes place over short
distances. Endocrine signals are carried long distances through the bloodstream by hormones,
and autocrine signals are received by the same cell that sent the signal or other nearby cells of the
same kind. Gap junctions allow small molecules, including signaling molecules, to flow between
neighboring cells.

Internal receptors are found in the cell cytoplasm. Here, they bind ligand molecules that cross the
plasma membrane; these receptor-ligand complexes move to the nucleus and interact directly
with cellular DNA. Cell-surface receptors transmit a signal from outside the cell to the
cytoplasm. Ion channel-linked receptors, when bound to their ligands, form a pore through the
plasma membrane through which certain ions can pass. G-protein-linked receptors interact with a
G-protein on the cytoplasmic side of the plasma membrane, promoting the exchange of bound
GDP for GTP and interacting with other enzymes or ion channels to transmit a signal. Enzyme-
linked receptors transmit a signal from outside the cell to an intracellular domain of a membrane-
bound enzyme. Ligand binding causes activation of the enzyme. Small hydrophobic ligands (like
steroids) are able to penetrate the plasma membrane and bind to internal receptors. Water-soluble
hydrophilic ligands are unable to pass through the membrane; instead, they bind to cell-surface
receptors, which transmit the signal to the inside of the cell.

Art Connections

Figure 9.1.79.1.7: HER2 is a receptor tyrosine kinase. In 30 percent of human breast cancers,
HER2 is permanently activated, resulting in unregulated cell division. Lapatinib, a drug used to
treat breast cancer, inhibits HER2 receptor tyrosine kinase autophosphorylation (the process by
which the receptor adds phosphates onto itself), thus reducing tumor growth by 50 percent.
Besides autophosphorylation, which of the following steps would be inhibited by Lapatinib?

A. Signaling molecule binding, dimerization, and the downstream cellular response.

B. Dimerization, and the downstream cellular response.
 C. The downstream cellular response.
D. Phosphatase activity, dimerization, and the downstream cellular response.
Answer

Footnotes
1. 1 A. B. Sigalov, The School of Nature. IV. Learning from Viruses, Self/Nonself 1, no. 4
(2010): 282-298. Y. Cao, X. Koh, L. Dong, X. Du, A. Wu, X. Ding, H. Deng, Y. Shu, J.
Chen, T. Jiang, Rapid Estimation of Binding Activity of Influenza Virus Hemagglutinin
to Human and Avian Receptors, PLoS One 6, no. 4 (2011): e18664.