Tampines Meridian Junior College

JC2 H2/9744 Biology 2024

Core Idea 3B
12. Energy and Equilibrium – Communication in Multicellular Organisms

SYLLABUS OVERVIEW
No. Overarching Idea Topics
1 Core Idea 1 Cell – The Basic Unit of Life
The Cell and Biomolecules
2 of Life Biomolecules of Life and Cellular Transport
Core Idea 3
3 Transformation of Energy – Photosynthesis and Cellular Respiration
Energy and Equilibrium
4 Genetics and Inheritance (I) – The Cell Cycle

5 Genetics and Inheritance (II) – DNA Replication and Gene Expression

6 Genetics and Inheritance (III) – DNA Mutations and their Consequences

7 Genetics and Inheritance (IV) – Molecular Techniques in DNA Analysis

Core Idea 2
Genetics and Inheritance (V) – Organization of Genome & Control of Gene
8 Genetics and Inheritance
Expression in Eukaryotes [Includes Core Idea 1D: Stem Cells]
Genetics and Inheritance (VI) – Organization and Inheritance of Viral
9
Genomes
Genetics and Inheritance (VII) – Organization of Genome & Control of Gene
10
Expression in Prokaryotes

11 Genetics and Inheritance (VIII) - Inheritance

Core Idea 3
12 Communication and Equilibrium in Multicellular Organisms
Energy and Equilibrium
Core Idea 4
13 Biological Evolution
Biological Evolution
Extension Topic A
14 Immunity and Infectious Diseases
Infectious Diseases
Extension Topic B
15 Impact of Climate Change Climate Change – Causes and Impacts on Animals and Plants
on Animals & Plants

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 What’s the Big Picture?

The following question should help students frame their learning:

• How do organisms respond to internal and external changes?

Communication is needed for organisms to respond to the environment and maintain equilibrium

Organisms should be able to detect changes both from the surrounding environment and within
themselves so that they are able to respond to these changes to maintain a constant internal
environment. This ability to respond to changes is made possible due to coordination across the
various biological systems as well as communication between cells.

Communication between cells can take the form of electrical or chemical transmission via the nervous
or endocrine system respectively. The endocrine system facilitates communication between different
cells through the release of hormones into the bloodstream. Binding of hormones to receptors on or
within target cells initiates signal transduction and eventually results in a change in gene expression
to bring about certain physiological changes. Defects in any part of the signalling pathway often lead
to detrimental conditions such as metabolic diseases and cancer.

Core Idea 3: Energy and Equilibrium

Topic B: Communication and Equilibrium in Organisms

The emphasis of this section is on how cell signalling processes can cause a physiological response in
an organism. The circulatory system transports hormones from where they are secreted to the target
cells. Hormones bind to specific binding sites – receptors found on the cell surface membrane or
within the cell – to initiate the process of cell signalling.

Cell signalling comprises the following stages: ligand-receptor interaction, signal transduction and
amplification, and cellular response. Various molecules such as second messengers, kinases and
transcription factors mediate the processes of converting information from the signal molecule
(hormone) into a cellular response. Insulin and glucagon are examples of hormones that trigger cell
signalling pathways to bring about responses to regulate blood glucose level.

It is important to appreciate the complexity and inter-connectedness of how the communication

systems within and between cells interact to achieve the required response. The maintenance of
blood glucose levels will be used to illustrate how physiological responses are regulated by
controlling gene expression. Sufficient glucose in the blood is necessary to provide cells with
respiratory substrates. The pancreas detects the level of blood glucose and secretes either insulin or
glucagon to maintain a stable level of glucose in blood. These hormones trigger cellular responses in
liver, muscle and adipose cells when the hormones bind to receptors. Signal transduction occurs
through various proteins and molecules to amplify and transduce the signal and eventually, elicit a
cellular response. Thus, cell signalling and communication result in a relatively stable internal
environment for cells in an organism to function optimally.

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LEARNING OUTCOMES
Core Idea 3B: Communication and Equilibrium in Organisms

Candidates should be able to:

a) Outline the main stages of cell signalling:

i. ligand-receptor interaction,
ii. signal transduction (phosphorylation cascade and signal amplification)
iii. cellular response (change in gene expression).
(Knowledge of intracellular receptors is not required.)

b) Explain the roles and nature of second messengers (including cyclic AMP).

c) Explain the role of kinases and phosphatases in signal amplification.

d) Outline how insulin and glucagon regulate the concentration of blood glucose level through the respective
tyrosine kinase receptor and G-protein linked receptor. (The outline should be limited to describing how
the ligand induces a conformational change in membrane-bound receptor to trigger downstream signalling
pathways that elicit physiological changes in blood glucose level. Details of different second messengers
and specific kinases activated in the pathway are not required).

Use the knowledge gained in this section in new situations or to solve related problems.

LECTURE OUTLINE

1. Overview
1.1 Why is Communication within the Multicellular Organism Important?
1.2 Types of Signal Molecules / Chemical Messengers
1.3 Types of Cell Signalling
1.4 Cell Signaling - How do cells receive and communicate signals?

2. Signal Reception
2.1 G Protein-Linked Receptor Signaling
2.2 Tyrosine Kinase Receptor Signaling
2.3 Ion Channel Receptor Signaling
2.4 Intracellular Receptor Signaling

3. Signal Transduction
3.1 Important Features
3.2 Transduction by Protein Phosphorylation and Dephosphorylation
3.3 Transduction by Second Messengers

4. Cellular Responses to Signals

4.1 Nature of Cellular Responses to Signals
4.2 Termination of Signal

5. Advantages and Significance of Cell Signaling Systems in Multicellular Organisms

6. Achieving Equilibrium in the Internal Environment of Multicellular Organisms

6.1 Overview
6.2 Regulation of Blood Glucose Concentration
(A) Regulation of Blood Glucose Concentration by Insulin
(B) Regulation of Blood Glucose Concentration by Glucagon

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REFERENCES

1. Reece, J., et al. (2014) Campbell Biology. Pearson Education, Inc., San Francisco, Tenth Edition. Pages
232 – 248.

2. Animations:
Introduction to cell
signalling

[Link]

Common cell signalling

pathways
(good overview!)

[Link]

Signal transduction

[Link]

G protein coupled
receptor

[Link]

[Link]

Second messengers:
cAMP

[Link]

Signal amplification

[Link]

[Link]

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 CELL SIGNALING – OVERVIEW
This table serves as an overview. You must refer to the notes for details.
You need to know the cell signalling pathways triggered in response to insulin and glucagon.
For other signalling pathways, you will need to draw upon your understanding of the molecules involved.

Possible types of cell surface membrane receptors:

• G protein-linked receptors
Step 1: Signal Reception • Tyrosine kinase receptors
Binding of signal molecules (ligands / • Ligand-gated ion channels
first messengers) with a shape
complementary to the binding site of Signal molecules that are hydrophilic cannot traverse the hydrophobic
receptors forms the ligand-receptor phospholipid bilayer, hence, need to bind to cell surface membrane
complex → receptor protein receptor. e.g. of cell surface membrane receptors - peptide hormones
undergoes conformation change such as insulin, glucagon and ions such Na+, K+, Cl-, etc.
and is activated

Possible types of signal transduction:

(1) Phosphorylation Cascade

• Involves activated protein kinases phosphorylating (adding
phosphate group) the next protein in cascade to activate the
Step 2: Signal Transduction inactive proteins.
Multi-step, cascaded pathways that • Involves protein phosphatases that remove phosphate groups
amplify and relay the signal received. to inactivate proteins.

(2) Transduction by 2nd messengers (e.g. cAMP)

Second messengers are small, non-protein molecules that relay
signals received by the receptors to activate intracellular pathways.

Possible types of cellular responses:

Step 3: Cellular Response NOTE: The type/s of cellular responses triggered depends on the
Various types of cellular responses signal that binds to the specific receptor (signal reception) and the
(e.g. gene expression, enzymatic subsequent enzyme/molecules activated (signal transduction)
processes) triggered in response to
the specific signal molecule (1) Expression of specific gene(s) to produce specific proteins

(2) Enzymatic pathways

Examples:
(a) Glycogenesis –
Glucose→glucose-6-phosphate → → → glycogen
(b) Glycogenolysis –
Glycogen → → →glucose

(3) Other Interactions among molecules (not in syllabus) e.g.

• interact with myosin leading to muscle contractions

Possible ways of signal termination:

Step 4: Signal Termination (1) At receptors
Cellular responses are terminated to • Chemical modification to inactivate receptors
ensure cell's continued • Inactivation of signalling proteins
responsiveness to incoming signals
• Down regulation via endocytosis / degradation by
lysosomes
(2) At relay proteins
• Hydrolysis of bound GTP to GDP by GTPase
• Converting cAMP to AMP by cAMP phosphodiesterase
• Increase phosphatase activity to inactivate relay proteins

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 1. Overview

1.1 Why is Communication within a Multicellular Organism Important?

Key Concept 1:
Cells in a multicellular organism must communicate through various chemical messengers to
coordinate their activities.

• In multicellular organisms, cell communication is important to allow for:

o multiple cell types to coordinate their activities to initiate a synchronized response.
o specialization of groups of cells.

• This communication is achieved by releasing chemical messengers / ligands / signal

molecules which may travel,
o short distances to influence cells in the vicinity (Fig. 1.1a), or long distances via the
circulatory system to influence cells distantly located (Fig. 1.1b),
o to target specific cells that will recognize and respond to the given messenger (Fig. 1.1a/b)

(a) (b)

Fig. 1.1: (a) Short-distant cell signaling. (b) Long-distant cell signaling via the bloodstream.

1.2 Types of Signal Molecules / Chemical Messengers / Ligands

• Signal molecules / ligands may be proteins, peptides or amino acids, nucleotides, steroids or
fatty acid derivatives and dissolved gases.

• A signal molecule that is hydrophilic/polar in nature (Fig. 1.2a) cannot traverse the
hydrophobic phospholipid bilayer of the cell surface membrane. Hence, it binds to receptor
molecules on the cell surface membrane.

• A signal molecule that is hydrophobic/non-polar in nature (Fig. 1.2b) can traverse the
hydrophobic phospholipid bilayer of the cell surface membrane and binds to intracellular
receptors within the cell. (not in syllabus)

Fig. 1.2 (a): Hydrophilic/polar hormone

secreted by a cell is carried in the bloodstream
(hydrophilic environment) unaided, eventually
exits the bloodstream and binds to the cell
surface receptor of another cell.

extracellular
Fig. 1.2 (b): Hydrophobic/non-polar hormone
intracellular secreted by a cell is carried in the bloodstream
with the help of a transport protein, eventually
exits the bloodstream, enters another cell and
binds to a intracellular receptor in the nucleus
of the cell.

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1.3 Types of Cell Signalling

• Cell signaling can be classified into 4 main categories.

a) Paracrine signaling
b) Autocrine signaling
c) Hormonal/endocrine signaling
d) Synaptic signaling between neurons of the nervous system (FYI only; not in syllabus)

a) Paracrine Signaling

• A type of local signaling where a secreting cell discharges substances (chemical signals)
into the interstitial/tissue fluid to act on nearby target cells (Fig. 1.3).

• These signal molecules are rapidly removed from the interstitial/tissue fluid to prevent them from
diffusing and exerting their effects over long distances.

• This removal occurs via

1. uptake by target cells
2. destruction by extracellular enzymes

• E.g. growth factors secreted by neutrophils during inflammation to stimulate cell growth and
division.

Fig. 1.3: Paracrine signaling – a secreting cell discharges chemical messengers into its vicinity,
which affects target cells but not non-target cells.

b) Autocrine Signaling

• Local signaling where a cell secretes signal molecules that bind to its own cell surface
receptors (Fig. 1.4).

• E.g. In response to bacterial antigens, monocytes (a type of leukocyte) secretes interleukin-1

(IL-1) which binds to its own cell surface receptor called IL-1 receptor.

Fig. 1.4: Autocrine signaling

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c) Hormonal / Endocrine Signaling

• Long-distance signaling where specialized endocrine cells secrete hormones into the
bloodstream and is transported in the blood to other cells in the body (Fig. 1.5).

• E.g. insulin secreted by the β cells of the Islets of Langerhans of the pancreas is transported by
the bloodstream to target liver cells and muscle cells.

Fig. 1.5: Hormonal/endocrine signaling – hormones are secreted directly

into the bloodstream by endocrine cells

1.4 Cell Signaling – How do cells receive and communicate the signals?

Key Concept 2:
Cell signaling ensures that crucial activities occur in the right cells, at the right time and in proper
coordination with the other cells of the organism.
It comprises 3 main stages: (1) signal reception, (2) transduction, (3) response.

• There are hundreds of different specific types of cell signaling pathways, but all of them share
the same features [(1) signal reception, (2) transduction, (3) response].

• Examples:
o Ras signaling in the regulation of cell division
o Glucagon and insulin signaling in the regulation of blood glucose concentration
o Cytokine signaling in the activation of gene transcription during immune response

1.4.1 Process

• Signal molecules/ligands are molecules that carries information from the environment. These
signal molecules bind specifically and reversibly to a complementary receptor to form the
receptor-ligand complex (reception). The information carried will then be converted into
another chemical form (transduced) inside the cell before the cell can respond (Fig. 1.6).

• Cell signaling involves 3 main stages: (1) signal reception, (2) transduction, (3) response.

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 Fig.1.6: The three main stages of cell signaling

1 Signal Reception

• Membrane receptors transfer information from the environment to the cell’s interior.

• A cell targeted by a particular chemical signal has receptor molecules at the cell surface
membrane which are complementary in shape to the signal molecule. Most of these signal
receptors are transmembrane proteins.

• The signal molecule is detected when it binds to the binding site of specific
complementary receptor protein.

• This interaction causes a conformational change in the receptor protein and activates it.

• The activated receptor then interacts with another molecule or aggregate with another
receptor molecule.

2 Transduction

• Transduction is induced by the activated receptor which converts the signal to specific cellular
responses via a cascade of reactions (i.e. a series of) that amplifies the signal.
o E.g. the phosphorylation cascade

• In some cases, transduction may occur in a single step.

3 Cellular Response

• The transduced signal triggers a specific cellular response.

• Examples:
o Enzyme catalysis (glycogen phosphorylase catalyses the breakdown of glycogen)
o Rearrangement of cytoskeleton (movement of synaptic vesicles containing
neurotransmitter)
o Activation of specific genes in the nucleus (testosterone or progesterone needed for
the development of secondary sexual characteristics).

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 2. Signal Reception

Receptors associated with membranes are known as membrane receptors, some examples include:
3. G protein-linked receptor (a.k.a. G protein-coupled receptor)
4. Tyrosine kinase receptor

Note: You are expected to use the knowledge gained in this section to apply to novel situations
involving other types of cell signaling.

2.1 G Protein-linked Receptor Signalling

a) Features of the G protein-linked receptor

• The G protein-linked receptor is a group of similar proteins that activate G protein.

• It is a cell surface membrane protein with 7 α-helices spanning the membrane. Specific loops
between the helices form binding sites for (Fig. 2.1):
1. extracellular signal molecule, and
2. intracellular G protein (a trimeric protein)

Fig. 2.1: The G Protein-linked receptor

• In turn, the G protein acts as an on-off switch

1. If GDP (guanosine diphosphate) is bound, the G protein is inactive
2. If GTP (guanosine triphosphate) is bound, the G protein is active

• Examples of G protein-linked receptors in different cell types include:

3. Olfactory neuron receptors of the nose – responsible for sense of smell
4. Rod photoreceptors of the eyes– responsible for sight
5. Glucagon receptors of the liver cells – responsible for glucagon-induced responses

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b) Signal Reception & Transduction (Fig. 2.2)

• When the ligand/signal molecule (e.g.

hormone glucagon) binds to the G protein-
linked receptor, the G Protein-linked receptor
changes conformation, becomes activated,
and binds to an inactive G protein in
membrane.

• This binding causes the G protein to

replace GDP with GTP, and is activated.

• The active G protein then dissociates

from the G protein-linked receptor, diffuses
along the membrane and binds to, alters the
conformation of another membrane
protein, often an enzyme.

These enzymes include:

• Adenylyl cyclase (most common)
o that converts ATP to cAMP, which in
turn triggers and lead to cellular
responses.
• Phospholipase C
o which splits PIP2 into IP3 and DAG,
which in turn triggers and lead to
cellular responses.

• After the extracellular signal is removed,

transduction is shut down by:

➢ deactivating the G protein.

The active G protein acts as a GTPase
enzyme and hydrolyzes the GTP to
GDP. This deactivates the G protein,
which then dissociates from the adenylyl
cyclase to prevent its action.

Other ways of termination of signal will be

covered in Section 4.2. Fig. 2.2: How the G Protein-linked receptor
signaling works

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2.2 Tyrosine Kinase Receptor Signaling

a) Features of the Tyrosine Kinase Receptor

• The tyrosine kinase receptor is a group of similar proteins with kinase activity and is capable
of phosphorylating tyrosine residues in the protein.

• A transmembrane protein with a single alpha helix spanning the membrane (Fig. 2.3) with:
1. an extracellular ligand binding site, and
2. an intracellular catalytic tail containing intrinsic tyrosine kinase (enzyme) and several
tyrosine residues. (Recall: tyrosine is an amino acid)

Fig. 2.3: Tyrosine kinase receptor Fig. 2.4: Tyrosine kinase tail phosphorylates the tyrosine
residues of intracellular tail of another tyrosine kinase receptor.

• The intracellular tyrosine kinase tail functions as a kinase enzyme that catalyzes the transfer
of phosphate groups from ATP molecules to tyrosine residues of intracellular tail of another
tyrosine kinase receptor (Fig. 2.4).

• The tyrosine kinase receptor system is effective in regulating and coordinating a variety of
activities, and triggering several signaling pathways simultaneously (e.g. during cell growth and
reproduction).

• Examples of tyrosine kinase receptors include:

o Insulin receptor
o Epidermal growth factor (EGF) receptor
o Fibroblast growth factor (FGF) receptor

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b) Tyrosine Kinase Receptor Signal Reception & Transduction Process (Fig. 2.5)

• 0 In the absence of extracellular signals, most tyrosine kinase receptors exist as monomers
where its kinase domain is inactive.

• When ligand /signal molecules (e.g. insulin) bind to the two receptor proteins, the receptors
dimerize to form a dimer.

• This dimerization activates the catalytic tyrosine kinase tail of each receptor protein to
cross-phosphorylates each other on multiple tyrosine residues.

• The fully-activated receptor dimer activates a variety of specific intracellular relay

proteins that recognize and bind to its specific phosphorylated tyrosine residues of the
cytoplasmic tails of the receptors.

• Relay proteins undergo structural changes triggering multiple responses simultaneously.

Fig. 2.5: Tyrosine Kinase Receptor signal reception and transduction

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2.3 Ion Channel Receptor Signaling

a) Features of Ion Channel Receptors

• The ligand-gated ion channel consists of transmembrane protein subunits (Fig. 2.6), with:
o an extracellular ligand/signal molecule binding site, and
o a gated hydrophilic channel which allows or blocks the flow of specific ions (e.g. Na+, K+
and Ca2+) through the receptor channel.

Fig. 2.6 The structure of a typical ion channel receptor

b) Ligand-Gated Ion Channel Receptor Signal Transduction Process (Fig. 2.7)

o When a ligand (e.g. acetylcholine) binds to the extracellular side of the receptor, it induces a
conformational change in the receptor, resulting in the opening of the channel.

o Ion flow changes its concentration inside the cell rapidly which in turn affects cellular
activity.

o When the ligand dissociates, the channel closes.

Fig. 2.7: How the ion channel receptor works

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2.4 Intracellular Receptor Signaling (details are not required in the syllabus)

a) Features of Intracellular Receptors

• These are signal receptors that are found in the cytosol (e.g. testosterone receptor) or in
the nucleus (e.g. thyroid hormone receptor) of target cells (Fig. 2.8).

• These receptors bind to ligands/signal molecules that are small (e.g. nitric oxide) and
hydrophobic in nature (e.g. steroid hormones such as testosterone and oestrogen).

• Serve as both intracellular receptors and effectors for the signal molecule

Fig. 2.8: Intracellular receptor signaling. The hormone-receptor complex acts as an effector (transcription
factor) which activates the transcription of genes.

b) Intracellular Receptor Signal Transduction Process (Fig. 2.8)

1) Signals which are usually steroidal in nature (e.g. steroid hormones) are able to directly
diffuse through the plasma membrane, bind to and activate intracellular receptor
proteins (either cytosolic or in nucleus, depending on the ligand).

2) These activated proteins (in the form of hormone-receptor complexes) enter the nucleus and
act as transcription factors that switches on specific genes, which are then transcribed
into messenger RNA (mRNA).

3) The mRNA molecules leave the nucleus and carry information that directs the synthesis of
specific proteins (via translation) at the ribosome.

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 3. Signal Transduction

Key Concept 3:
Signal Transduction is a multistep, cascaded pathway that amplifies the signal by
(i) phosphorylation–dephosphorylation reactions and/or (ii) second messengers.

3.1 Important Features

• In a signal transduction pathway, the signal molecule is not passed along the pathway. Instead,
information is passed on by molecules that relay the signal in multistep processes such as

o Phosphorylation-dephosphorylation reactions of subsequent proteins in the signal

transduction pathway

and/or

o Second messengers (e.g. cyclic AMP)

• This relaying of signals is a multistep process that allows for greater fine-tuning of cellular
responses and for amplification of the signal. Such a series of signal amplification is known as
cascade amplification (Fig. 3.1)

o Each catalytic step in a cascade produces a larger number of activated products than in
the preceding step.

o Thus, a very small amount of signal will give a large response as each activated enzyme
molecule can convert many substrate molecules into products per unit time before being
inactivated.

Fig. 3.1: Signal amplification

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3.2 Transduction by Protein Phosphorylation and Dephosphorylation

• Protein phosphorylation is the transfer of phosphate groups from ATP to a target protein by
protein kinase. The phosphorylation causes the target protein to undergo a conformational
change and convert from the inactive to active form.

• It is a widespread cellular mechanism for regulating protein activity. It can also be seen as a
post-translational control of gene expression.

• The protein kinases act on amino acid serine or threonine of its substrate (usually another
protein kinase) in a signal transduction pathway leading to a phosphorylation cascade (Fig.
3.2).

Fig. 3.2: A phosphorylation cascade

• A phosphorylation cascade is sequence of phosphorylation reactions where the activated

relay protein phosphorylates and activates a protein kinase which in turn phosphorylates and
activates the subsequent protein kinase leading to an amplified and divergent cellular
response.

• Conversely, protein phosphatases remove phosphate groups from proteins thus

inactivating protein kinases, in the absence of the extracellular signal. This consequently turns
off the signal transduction pathway.

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3.3 Transduction by Second Messengers

a) Nature of second messengers

• Are small, non-protein molecules or ions which may be:

o water-soluble and rapidly diffuse throughout the cell (e.g. cAMP, Ca2+ ions and inositol
triphosphate, IP3),

OR

o lipid-soluble and diffuse within the plasma membrane (e.g. diacylglycerol, DAG).

b) Roles of second messengers

• Second messengers relay information from the receptor-ligand complex to other proteins in
the transduction pathway.

o They bind to and alter the conformation of other proteins, hence, elicit a response to the
signal.

• Second messengers participate in pathways initiated by both G protein-linked receptors and

tyrosine kinase receptors.

• They are short-lived because they are eventually removed or sequestrated from the cytosol.

Examples:
o Phosphodiesterase converts cAMP to AMP (Fig. 3.3a), thus reducing their concentration in
the cytosol.
o Cytosolic Ca2+ is pumped back into the ER or out of the cell (Fig. 3.3b), thus sequestrating
them from the cytosol.

Fig. 3.3a: Upon signal reception, membrane-anchored adenylyl cyclase converts ATP to cAMP, which acts as a second
messenger for downstream signaling. cAMP is eventually converted to AMP by cAMP phosphodiesterase.

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 Fig. 3.3b: Calcium ion sequestration from the cytosol.

c) Examples of second messengers

1. Cyclic AMP (cAMP)

• When a signal molecule such as the hormone adrenaline or glucagon binds to the G protein-
linked receptors, G-protein is activated, which in turn, binds to and activates adenylyl
cyclase in the plasma membrane (Fig. 3.4).

• Activated adenylyl cyclase catalyses the conversion of ATP to cAMP.

• The cAMP acts as a second messenger and diffuses throughout the cell and activates
protein kinase A (a cAMP-dependent protein kinase).

• This in turn phosphorylates other proteins which activates transcription of target genes.

• The cAMP is then rapidly hydrolysed by cAMP phosphodiesterases to form AMP.

Fig. 3.4: cAMP as the second messenger.

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 2. Calcium ions (details not required in syllabus)

• Normally, Ca2+ is maintained at a much lower concentration in the cytosol than in the
extracellular/tissue/interstitial fluid, endoplasmic reticulum, and under certain conditions, the
mitochondria and chloroplast.

• This is due to the active transport of Ca2+ from the cytosol into the
extracellular/tissue/interstitial fluid and these organelles by various protein pumps.

• Cytosolic Ca2+ can be increased in 2 ways:

o cAMP activates the opening of plasma membrane Ca2+ channels allowing facilitated
diffusion of extracellular Ca2+ into the cytosol (e.g. in olfactory sensory neurons).

o IP3 (inositol trisphosphate) activates the release of intracellular store of Ca2+ in the
endoplasmic reticulum (Fig. 3.5):

1. A signal molecule binds to G-protein linked membrane receptors or tyrosine kinase

receptors and activates phospholipase C.

2. Phospholipase C in turn cleaves a membrane phospholipid (PIP2) to give two other

second messengers, diacylglycerol (DAG) and inositol trisphosphate (IP3).

3. IP3 diffuses through the cytosol, binds to, activates and opens IP3-gated Ca2+
channels on the endoplasmic reticulum (ER) membrane, releasing Ca2+ from the
ER thereby increasing cytosolic Ca2+ concentration.

4. Ca2+ ions also acts in a positive feedback loop where increased cytosolic Ca2+
activate more IP3-gated Ca2+ channels triggering the release of more Ca2+ stores,
thus amplifying the response.

5. DAG and Ca2+ ions also participate in the activation of protein kinase C which
phosphorylates specific target proteins.

Fig. 3.5: How the calcium ion store in the ER can be released into the cytosol.

• An increase in cytosolic Ca2+ concentration usually activates a wide variety of enzymatic

processes e.g. smooth muscle contraction, exocytosis and glycogen metabolism.

• Ca2+ ions are eventually pumped out of the cell into the extracellular fluid or back into the ER to
terminate the initial Ca2+ response and restore the low cytosolic Ca2+ concentration.
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 4. Cellular Responses to Signals

4.1 Nature of Cellular Responses to Signals

Key Concept 4:
The type(s) of cellular responses (e.g. cell metabolism and protein synthesis) triggered depends
on (a) the signal and the type of receptor that it binds to (signal reception) and (b) the subsequent
enzyme/molecules activated (signal transduction).

a) Cells respond to signals by

• by regulating protein and enzyme activities in the cytoplasm, hence changing its
metabolism;
• gene expression through transcription factors in the nucleus (Fig. 4.1)

Fig. 4.1: Cytoplasmic or transcriptional responses to signals

b) Various types of cells may receive the same signal but respond very differently (Fig. 4.2).

• The response of a target cell to a signal depends on the particular collection of receptor
proteins, relay proteins, and other proteins that are present to carry out the response.

Fig. 4.2: How a signal molecule can give rise to different cellular response in different cell types.
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 • Examples:

o Adrenaline triggers liver or skeletal muscle cells to break down glycogen, but
stimulate cardiac muscle cells to contract, leading to a rapid heartbeat.

o Acetylcholine decreases rate and force of contraction in cardiac muscles but stimulates
contraction of skeletal muscle & secretion of enzymes by salivary gland.

c) Same cell with different receptors can receive different signals to trigger a coordinated
cellular response. Branching of pathways and interactions (“cross-talk”) between pathways
(Fig. 4.2, Cell C) allow fine-tuned regulation and coordination of a cell’s response to
incoming information from different sources.

d) The efficiency of signal transduction may be increased by the presence of scaffold proteins
(Fig. 4.3).

Fig. 4.3: The presence of a scaffold protein facilitates the signaling cascade.

• Scaffold proteins are large relay proteins to which several other relay proteins (usually protein
kinases) are simultaneously attached.

• Scaffolding proteins facilitate the activation of specific phosphorylation cascade(s) thereby

enhancing the speed and accuracy of signal transfer between intracellular proteins.

• Some scaffolding proteins also participate in more than one pathway in different cell types or
at different times in the same cell thus forming a complex signaling network.

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4.2 Termination of Signal

• The purpose of signal termination is to ensure cell’s continued responsiveness to incoming

signals.

• Cells can terminate signals by acting on the receptors or the relay proteins along the pathways.
Examples include (Fig. 4.4):

o Receptor sequestration – the receptor can be internalized into the cell via endocytosis.
This reduces the number of available receptors on the cell surface for the ligands to bind to.
The sequestrated receptor could be recycled to the cell surface for use.

o Receptor down-regulation – Internalized receptor is sent to the lysosomes for

degradation.

o Receptor inactivation – The receptor can be inactivated via chemical modification to its
intracellular tail. The receptor is hence unable to activate other intracellular signaling proteins.

o Inactivation of signaling protein – The intracellular signaling protein can be inactivated via
chemical modification. It is hence unable to activate other intracellular signaling proteins.

o When the signal molecule detaches from the receptor, the receptor and relay molecules
revert back to their inactive form:

1. GTPase hydrolyses its bound GTP to GDP.

2. cAMP phosphodiesterase converts cAMP to AMP.
3. Protein phosphatases removes phosphate groups from the phosphorylated kinases
and other proteins, thus, inactivating these protein molecules.

Fig. 4.4: Some ways in which target cells can become desensitized to an extracellular signal molecule.

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 5. Advantages and Significance of Cell Signaling Systems
in Multicellular Organisms

1. Signal amplification (Fig. 3.1) – A very small amount of signal is sufficient to give a large
response because each catalytic step in a cascade produces a larger number of activated
products than in the preceding step.

2. Regulated and controlled cellular response – The multi-step signaling cascade enables a
greater fine-tuning and control as each enzyme-catalyzed step can be controlled independently
of the preceding steps, ensuring an appropriate cellular response. In addition, signal termination
(Section 4.2) ensures that ligand reception will not lead to unintended prolonged cellular
responses.

3. Specificity – Each ligand is specific only to certain receptor(s) found on certain cell type(s). This
ensures that only the appropriate cells are being targeted. For example, the hormone
erythropoietin (Epo) is only specific to erythropoietin receptor (EpoR) found on bone marrow
stem cells, which then differentiate to give erythrocytes.

4. Reception on the cell surface membrane can lead to activation of genes in the nucleus –
Many ligands are hydrophilic in nature. Cell signaling system ensures that these ligands are able
to activate gene transcription even though they are unable to traverse through the hydrophobic
core of the cell membrane into the cell.

5. A single signal molecule can trigger numerous cellular reactions at once – At certain point,
the signaling pathway may branch off (Fig. 4.2, Cell B) such that different kinds of intracellular
signaling proteins are activated. These activated proteins then activate the respective sets of
genes, leading to different cellular response.

6. Coordinated cellular response – Coordinated responses can be initiated within the same cell
responding to different ligands at the same time due to interactions (“cross-talk”) between the
different pathways activated by the different receptors (Fig. 4.2, Cell C).

7. A single type of signal molecule can activate many different cell types simultaneously to
trigger numerous different cellular reactions at once

o e.g. Adrenaline triggers liver or striated muscle cells to break down glycogen, but stimulate
cardiac muscle cells to contract, leading to a rapid heartbeat

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 6. Achieving Equilibrium in the Internal Environment

6.1 Overview

• For optimal function, the internal environment of an organism needs to be maintained constant
(within narrow limits) despite changes in the external environment.

• The internal environment refers to the intracellular (inside the cell) and extracellular (in the
tissue fluid surrounding the cell) environment of the body.

• Some important parameters in the internal environment include

o Temperature
▪ Low temperatures inactivate enzymes, hence, slowing metabolic reactions.
▪ High temperatures denature proteins and enzymes.

o pH
▪ The pH of blood and tissue fluid, as well as the pH of cytosol, has to be kept within narrow
limits to prevent denaturation of enzymes and proteins.

o Concentration of glucose
▪ Glucose is the primary respiratory substrate. A lack of it causes respiration to slow down
or stop.
▪ Excess blood glucose (a solute) may cause water to leave cells into the blood by
osmosis. Excessive retention of water in the blood can cause high blood pressure.

o Volume of water in the blood

▪ Lack of water in the tissue fluid causes water to leave the cells by osmosis, causing
metabolic reactions to slow down or to stop.
▪ Too much water entering the cell may cause dilution of metabolites.

• Thus, maintaining an equilibrium in the internal environment is important to :

o ensure that enzymes and metabolic processes can function optimally for organisms to live
and reproduce.
o ensure that limits are not exceeded, hence, preventing dangerous fluctuations.
o provide the organism with a degree of independence of the external environment.

• The roles of signal molecules in maintaining this equilibrium is illustrated in Sections 6.2 and 6.3.
The signal molecules are a pair of protein hormones, insulin and glucagon, which act
antagonistically to maintain blood glucose concentration within the tight limit of 70-110 mg
glucose /100ml blood. The normal level or set point of blood glucose is 90 mg /100ml blood.

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6.2 Case Study: Regulation of Blood Glucose Concentration by Insulin Signaling

(A) Regulation of blood glucose level by Insulin Signaling in Liver and Muscle Cells (Fig. 6.1)

• When blood glucose level rises above the set point of 90mg glucose /100m of blood (e.g. after
a meal), insulin is released by  cells of the Islets of Langerhans of pancreas to bring about
responses in liver cells, muscle cells and other respiring cells that would lower blood glucose
level back to the set point:

Fig. 6.1a: Insulin receptor signaling

1. Two insulin molecules bind to the complementary -subunits of 2 insulin receptors on the
cell surface membrane of liver and muscle cells.

This binding triggers a conformation change in the receptors, and the 2 receptors dimerized.

2. The activated dimer causes the -subunit of the insulin receptor to transmit a signal to the
catalytic tyrosine kinase tail of each receptor protein.

3. The tyrosine kinase cross-phosphorylates each other on multiple tyrosine residues, fully
activating the insulin receptor.

The fully activated insulin receptor then activates the insulin receptor substrate (IRS).

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4. Activated IRS in turn, trigger a variety of relay proteins (Fig. 6.1b), resulting in various cellular
responses:

• ↑ in rate of processes that remove glucose from the blood →

o ↑ transport of glucose transporters to cell surface membrane to increase glucose uptake
into the cell
o ↑ glycogenesis (synthesis of glycogen from glucose for storage)
o ↑ glycolysis (oxidation of glucose), hence increased ATP synthesis
o ↑ fatty acid synthesis

• ↓ in rate of processes that return glucose to the blood →

o ↓ glycogenolysis (hydrolysis of glycogen to glucose)
o ↓ gluconeogenesis (conversion of non-carbohydrate sources to glucose)

• These responses decrease blood glucose concentration back to the set-point.

Fig. 6.1b shows a detailed example of a insulin receptor signalling pathway.

Fig. 6.1b: Detailed example of an insulin receptor signaling pathway

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(B) Regulation of blood glucose level by Glucagon Signaling In Liver Cells (Fig. 6.2 and 6.3)

• When blood glucose level falls below the set point (e.g. during fasting), glucagon is released
by  cells of the Islets of Langerhans of pancreas to bring about responses in liver cells (but
NOT muscle cells).

• In the liver cell, glucagon activates different transduction pathways to bring about the same
set of cellular responses that release glucose back to the blood to restore the set point.

Transduction pathway via cAMP as second messenger (Fig. 6.2)

1. Glucagon binds to complementary G protein-linked receptor, activating the receptor.

Activated receptor binds to an inactive G protein in membrane.

2. The binding causes the G protein to replace GDP with GTP and becomes activated. The (-
subunit of) activated G protein then diffuses along the membrane and bind to adenylyl
cyclase.

3. Adenylyl cyclase becomes activated and catalyses the synthesis of cAMP from ATP.

4. Increased cytosolic concentration of cAMP activates protein kinase A (PKA),

5. PKA in turn, phosphorylates and activate other proteins, which results in

a. ↑ gluconeogenesis and glycogenolysis,
b. ↓ of glycolysis and glycogenesis.
c. Eventually, resulting in increased blood glucose concentration back to the set-point.

Fig. 6.2: Glucagon signaling pathway involving cAMP as second messenger.

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Transduction pathway via Calcium Ions as second messenger (Fig. 6.3) (details not required)

1. Upon binding of glucagon to the G protein-linked receptor (G protein-linked glucagon

receptor), the receptor becomes activated and binds to an inactive G protein in membrane.

2. This activates another G-protein which in turn activates phospholipase C.

3. Phospholipase C in turn cleaves a membrane phospholipid (PIP2) into two other second
messengers:

• Diacylglycerol (DAG) – activates protein kinase C (PKC)

• Inositol trisphosphate (IP3) – binds to and opens the calcium channel on the ER, thus
increasing cytosolic Ca2+ concentration

4. Increased cytosolic Ca2+ concentration and activated PKC increases gluconeogenesis and
glycogenolysis and inhibits glycolysis and glycogenesis.

Fig. 6.3: Glucagon signaling involving IP3, DAG and Ca2+ as the second messengers.
(details not required by syllabus)

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 Summary Map on Control of Blood Glucose Level by Insulin & Glucagon

3 Main Stages of Cell By Insulin By Glucagon

Signalling:
An increase in blood sugar level above set point A decrease in blood sugar level below set point
(90mg/100ml of blood) (90mg/100ml of blood)
↓ ↓
Is detected by the beta cells of islets of Langerhans Is detected by the alpha cells of islets of Langerhans
of pancreas of pancreas
↓ ↓
Which secretes insulin (1st messenger) Which secretes glucagon (1st messenger)
↓ ↓
1. Signal Reception 2 insulin molecules bind to the complementary Glucagon binds to complementary G-protein linked
receptor tyrosine kinase (RTK) on the liver (or receptor (GPLR) on liver cell
muscle) cell
↓ ↓
This binding causes RTK to undergo changes in This binding causes GPLR to undergo changes in
conformation and form a dimer conformation.
↓ ↓
The dimer activates the catalytic tyrosine kinase tail This conformational change causes the GPLR to be
to cross-phosphorylate each other on tyrosine activated and binds to an inactive G protein
residues
↓ ↓
2. Signal Transduction The activated receptors in turn activates the The binding causes the inactive G protein to replace
downstream signal proteins such as protein kinases GDP with GTP and G protein becomes activated.
↓
The activated G-protein will then diffuse along the
membrane and bind to adenyl cyclase to activate it
↓
Activated adenyl cyclase will convert ATP to cyclic
AMP (cAMP), the 2nd messenger, which activates
protein kinase A (PKA). Activated PKA in turn
activates target enzymes by phosphorylating them.
↓ ↓
Thus a phosphorylation cascade is initiated. Thus a phosphorylation cascade is initiated.
3. Cellular Response Phosphorylation activates protein kinase in a cascade Protein kinase A activates phosphorylase kinase
which eventually activates glycogen synthase which which activates glycogen phosphorylase which
catalyses glycogen synthesis from glucose (i.e. catalyses glucose synthesis from glycogen (i.e.
increase glycogenesis in liver and muscle) glycogenolysis)

Other cellular responses also occur Other cellular responses also occur.
Examples: Example:
1. Translocation of glucose transporters from 1. Increased gluconeogenesis (synthesis of
cytoplasmic vesicles to the cell membrane. Hence glucose from non-carbohydrate sources).
increased glucose uptake into cells. 2. Inhibit glycolysis and glycogenesis
2. Increased rate of glycolysis (i.e. oxidation of
glucose)
3. Increased lipid & protein synthesis
4. Inhibit gluconeogenesis and glycogenolysis

↓ ↓
Thus blood glucose levels decreases to set point Thus blood glucose level increases.
(90mg/100ml of blood)
↓ ↓
This is detected by the beta cells of islets of This is detected by the receptor (detector, i.e. alpha
Langerhans which then decreases insulin cells) which then decreases glucagon production.
production.
4. Signal Termination Cellular responses can be terminated by acting on the:
(1) Receptors
• Chemical modification to inactivate receptors
• Inactivation of signalling proteins
• Down regulation via endocytosis / degradation by lysosomes
(2) Relay proteins
• Hydrolysis of bound GTP to GDP by GTPase
• Converting cAMP to AMP by cAMP phosphodiesterase
• Increase phosphatase activity to inactive relay proteins

Advantages of multi-step signal cascade:

1. Greatly amplifies the signal
• Each step in a cascade produces a larger number of activated products than in the preceding step
• Thus, a very small amount of signal will give a large cellular response
2. Allows for greater fine-tuning of cellular responses
 End of Notes 
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