Signal Transduction

What is Signal Transduction?

• The human body is made up of trillions of cells that need to communicate to

function as a coordinated unit.

• Signal transduction is the process by which cells send and receive messages to
regulate various functions such as metabolism, growth, immune response, and
more.

• Think of it as a phone network inside the body—messages (signals) are sent,

received, and interpreted.

Why is it Important?

• It controls almost every physiological process.

• Errors in signal transduction pathways can lead to diseases like cancer,

diabetes, and neurodegenerative disorders.

A Signaling Molecule (Ligand): This is like a text message being sent.

A Receptor: This is like a phone receiving the message.

Paracrine Signaling – A cell sends signals to nearby cells by releasing molecules into
the surrounding area. Only the nearby cells respond.

Endocrine Signaling – A cell releases hormones into the bloodstream, allowing them
to travel throughout the body. However, only cells with the right receptors will react.

Neural Signaling – A nerve cell sends electrical signals along its length. When it
reaches the end, it releases a chemical (neurotransmitter) that passes the message to
another nerve, a muscle, or a gland.

Autocrine Signaling – A cell sends signals to itself. This is often seen in growth
regulation, but if it goes out of control, it can lead to tumors.

An agonist is a drug that binds to a receptor and activates it.

An antagonist is a drug that binds to a receptor without activating it, but instead,
blocks the receptor from being activated by other chemicals in the body.

A great analogy is a lock & key. The body’s natural chemicals are like the original
key used to open a lock. Drugs that are agonists are similar to a good spare key that will
mimic a similar response to the original key, opening the lock. An antagonist is a poorly
made spare key that doesn’t open the lock, jams the keyhole, & prevents the original key
from being used at all.

Receptor Specificity:

Receptor specificity means that a receptor only responds to a specific type of molecule
(ligand), just like a lock only opens with the right key.

• Only the Right Fit – A receptor will only recognize and bind to certain molecules,
similar to how your phone only unlocks with your fingerprint or password.

• Shape Matters – The shape of the ligand must match the receptor for binding to
happen. If it doesn’t fit, there’s no response.

• Selective Activation – Even if many signals are present in the body, a receptor
will only react to the one it is designed for, ensuring proper communication
between cells.

Receptor Affinity:

Receptor affinity refers to how strongly a receptor binds to a ligand (signal molecule).

• Strong vs. Weak Binding – If a receptor has high affinity, it holds onto the ligand
tightly, like a magnet sticking to metal. If it has low affinity, the ligand binds
loosely and can easily detach.

• Efficient Signaling – High-affinity receptors can detect and respond to even

small amounts of a ligand, while low-affinity receptors need more of the ligand to
produce a response.

Ionotropic receptors are proteins found on the surface of cells that act like gated
channels for ions (charged particles) to pass through.

• They are activated by neurotransmitters (chemical messengers in the brain and

nervous system).

• When a neurotransmitter binds, the receptor opens up like a gate, allowing

specific ions (like Na⁺, K⁺, Cl⁻, or Ca²⁺) to flow into or out of the cell.

• This changes the electrical state of the cell, leading to a fast response.

Fast and Direct Action – Unlike other receptors that use complex signaling
pathways, ionotropic receptors work immediately by opening channels directly when
activated.

Nicotinic receptors – 5 subunits around a central pore –stimulated by acetylcholine

• Gamma-amino-butyric acid A (GABAA-R) similar to nicotinic receptor - selective for
anions esp Cl-

• Glutamate – excitatory amino acid neurotransmitter found in CNS – two classes of

glutamate receptors – NMDA (N-methyl-D-aspartate) and non NMDA receptors – Ligand
gated channels that are voltage gated – For ions to flow the receptor must bind
glutamate and be depolarised – Allows for significant influx of Ca2+

GPCR & Metabotropic Meaning

• GPCR (G-Protein Coupled Receptors) are a type of receptor that activates G

proteins inside the cell when a ligand (signal molecule) binds to them.

• Metabotropic means that the receptor does not directly open ion channels (like
ionotropic receptors) but instead triggers chemical signaling pathways inside
the cell.

• These pathways take longer but lead to complex and longer-lasting effects, such
as activating enzymes or changing gene expression.

• • Ligand Binding – A signaling molecule (ligand) binds to the GPCR.

• • Enzyme Activation – The GPCR activates an enzyme, which causes a change in
the αβγ heterotrimer.
• • Subunit Separation – The α subunit separates from the βγ subunits, and both
parts become active.
• • Signal Transmission – The α and βγ subunits move through the membrane and
interact with enzymes and ion channels to pass on the signal.
• • Second Messengers – These interactions lead to the production of second
messengers, which are small molecules inside the cell that amplify the signal and
create various cellular responses.

• What Are Second Messengers?

• Second messengers are molecules that help relay and amplify signals inside the cell.
Examples:
✔ cAMP (Cyclic AMP) – Activates enzymes and controls processes like metabolism.
✔ IP₃ (Inositol triphosphate) – Helps release calcium (Ca²⁺) from storage inside the
cell.
✔ DAG (Diacylglycerol) – Works with IP₃ to activate proteins.
✔ Ca²⁺ (Calcium ions) – Acts as a signal for many processes, including muscle

COMPONENTS

cAMP & Adenylate Cyclase

 • cAMP (Cyclic Adenosine Monophosphate) is a second messenger that helps pass
signals inside the cell.
• It is produced when an enzyme called adenylate cyclase converts ATP (energy
molecule) into cAMP.
• cAMP then activates PKA (Protein Kinase A), which triggers various cellular
processes like metabolism, gene expression, and muscle contraction.

Think of adenylate cyclase as a factory that makes cAMP, and cAMP as a

messenger that tells the cell what to do!

2. Guanylate Cyclase & cGMP

• Guanylate Cyclase is an enzyme that converts GTP (Guanosine Triphosphate) into

cGMP (Cyclic GMP).
• cGMP (Cyclic Guanosine Monophosphate) is another second messenger, similar
to cAMP, but used in different pathways.
• It is important for relaxing blood vessels (vasodilation), controlling vision in the
retina, and regulating cell growth.
• Example: Nitric oxide (NO) activates guanylate cyclase, increasing cGMP levels to
relax blood vessels (how some blood pressure medications work).

If cAMP is like a text message, cGMP is like an email—both send signals but for
different jobs!

3. Phospholipase C (PLC), IP₃, and DAG

• Phospholipase C (PLC) is an enzyme that breaks down a membrane lipid (PIP₂) into
two important second messengers:
1. IP₃ (Inositol Triphosphate) – Triggers the release of Ca²⁺ (calcium ions)
from inside the cell, which helps in muscle contraction, neurotransmitter
release, and other functions.
2. DAG (Diacylglycerol) – Stays in the membrane and activates PKC (Protein
Kinase C), which controls cell growth, metabolism, and immune responses.

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How Signal Amplification Works:

1. One ligand (signal molecule) binds to a receptor.

2. That receptor activates multiple G proteins (up to 20!).

3. Each G protein activates an enzyme (like adenylate cyclase).

4. Each enzyme produces many second messengers (like cAMP).

5. Each second messenger activates more enzymes (like PKA).

 6. This triggers a cascade where each step amplifies the signal.

Key Idea: A single signal multiplies as it moves down the pathway, allowing
the cell to respond strongly to even tiny amounts of a signal.

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What Are Enzyme-Linked Receptors?

These are special receptors that also function as enzymes inside the cell.

• They sit on the cell membrane and have two main parts:

1. Extracellular domain (outside the cell) – Binds to a ligand (signal

molecule).

2. Intracellular domain (inside the cell) – Acts as an enzyme when

activated.

• They are activated by hormones and growth factors like insulin, cytokines,
leptin, and platelet-derived growth factor (PDGF).

How Do They Work?

1. A ligand (like insulin) binds to the receptor outside the cell.

2. The receptor’s intracellular part gets activated and acts like an enzyme.

3. This enzyme is a kinase (it adds phosphate groups to proteins).

4. Adding phosphate groups activates signaling pathways that control cell

growth, differentiation, immune response, and metabolism.

Types of Kinases in These Receptors

• Tyrosine Kinase – Adds phosphate groups to tyrosine (a specific amino acid).

o Example: Insulin receptor, Growth Factor receptors (important in cancer

research).

• Guanylate Kinase – Produces cGMP, another signaling molecule.

What Are Intracellular Receptors?

• Unlike other receptors (GPCRs & enzyme-linked receptors) that sit on the
cell membrane, these receptors are inside the cell, either in the cytoplasm or
nucleus.
• Their main job is to directly control gene expression by turning genes on or off.

How Do They Work?

1. Ligands (signal molecules) are lipid-soluble (e.g., steroid hormones like

estrogen, cortisol, testosterone).

2. Because they are lipid-soluble, they can pass through the cell membrane
easily.

3. Once inside, the ligand binds to an intracellular receptor (which is inactive and
attached to heat shock proteins).

4. Binding activates the receptor, and it moves into the nucleus.

5. Inside the nucleus, the receptor binds to specific hormone response elements
(HREs) on DNA using zinc fingers (DNA-binding regions of the receptor).

6. This either activates or inhibits gene expression, leading to the production (or
suppression) of certain proteins.

Cessation of Activity in Signal Transduction Pathways

What does it mean?

• Signal transduction pathways (the signaling process in cells) don’t just keep
going forever. At some point, they need to stop so the cell doesn’t get
overstimulated, which could cause harm.

• Once the cell has responded to a signal, the signal needs to be turned off. This
is important because chronic overstimulation (too much signal over a long
time) can lead to problems like cancer, inflammation, or cell damage.

• The main goal is to stop receptor activation so that the cell can return to
normal functioning.

How Does Signal Transduction Activity End?

1. Decrease in the concentration of the first messenger:

o The first messenger (the signaling molecule, like a hormone or

neurotransmitter) that started the signal must be removed or reduced.

o How?

▪ Enzymes nearby break down the first messenger.

 ▪ The first messenger can be taken up by nearby cells.

▪ Or, it can diffuse away (move away) from the area where the
receptor is located.

2. Receptors Can Be Inactivated in Other Ways:

o Phosphorylation of the receptor – This is when a phosphate group is

added to the receptor, and this lowers the receptor’s ability to bind the
first messenger (meaning the signal is stopped). The receptor becomes
less active and releases the messenger.

o Phosphorylation prevents further G protein binding – If the receptor is

phosphorylated, it prevents G proteins from continuing to bind to the
receptor. Since G proteins are responsible for passing the signal inside
the cell, this stops the signaling pathway.

o Endocytosis of the receptor – Sometimes, the combination of the first

messenger and the receptor is taken into the cell by endocytosis (the
cell “eats” it up). This physically removes the receptor from the surface of
the cell, and no more signals can be received.

SUMMARY

Types of Cell Signalling

• Paracrine: Signaling happens locally between nearby cells.

• Endocrine: Hormones are released into the bloodstream and travel throughout
the body to affect distant cells.

• Neural: Signals travel through nerve cells, either affecting the same cell
(autocrine) or nearby cells (paracrine).

• Autocrine: Cells signal to themselves, typically seen in growth factors.

GPCR – G-Protein Coupled Receptors

• GPCRs are receptors on the cell surface that, when activated, trigger a chain of
events inside the cell using G proteins.

• They activate second messengers (like cAMP or IP3) that spread the signal and
amplify the response.

5. Second Messenger Systems

• cAMP (Cyclic AMP): A second messenger that activates protein kinase A (PKA),
leading to a wide range of cellular responses (like gene activation).
• cGMP (Cyclic GMP): Another second messenger that acts similarly to cAMP but
is involved in different signaling pathways (like in smooth muscle relaxation).

• Phospholipase C: An enzyme that, when activated by a GPCR, creates second

messengers like IP3 and DAG, which help control processes like calcium
release and cell growth.

6. Intracellular Receptors

• These receptors are located inside the cell (either in the cytoplasm or nucleus).

• Lipid-soluble ligands (like steroid hormones) can pass through the cell
membrane and bind to these receptors.

• Once bound, the receptor directly interacts with DNA, either activating or
inhibiting genes to regulate protein synthesis.