• The first step of hormone action is binding of the hormone to a specific receptor on or inside the target cell.
• A cell without the correct receptor does not respond to that hormone.
• Hormone receptors may be located on the cell membrane, in the cytoplasm, or in the nucleus.
• Hormone-receptor binding usually starts a cascade of cellular reactions, where each step amplifies the next.
• Therefore, even a small amount of hormone can produce a large effect.
• Hormone receptors are large proteins.
• A target cell may have about 2,000–100,000 receptors.
• Usually, each receptor is highly specific for one hormone.
• Therefore, a tissue responds to a hormone only when it has the specific receptor for that hormone.
• The main receptor locations are:
  • Cell membrane: mainly for protein, peptide, and catecholamine hormones.
  • Cytoplasm: mainly for steroid hormones.
  • Nucleus: for thyroid hormones, whose receptors are associated with chromosomes.
• The Number and Sensitivity of Hormone Receptors Are Regulated
  • The number of active receptors in a target cell can change from day to day or even minute to minute.
  • Receptors may be inactivated or destroyed, while others may be reactivated or newly produced.
  • Increased hormone concentration and increased receptor binding can sometimes cause the number of active receptors to decrease.
  • This is called down-regulation.
  • Down-regulation can occur through:
    • Inactivation of receptor molecules.
    • Inactivation of intracellular signaling molecules.
    • Temporary movement of receptors inside the cell, away from the hormone.
    • Destruction of internalized receptors by lysosomes.
    • Decreased production of new receptors.
  • Result: down-regulation → fewer active receptors → decreased tissue responsiveness to the hormone.
• Some hormones cause up-regulation of receptors and intracellular signaling proteins.
• In up-regulation, the hormone causes the target cell to produce more receptors or signaling molecules, or makes more receptors available to interact with the hormone.
• Result: up-regulation → more receptor availability → increased tissue sensitivity to the hormone.

KEY CONCEPT

Hormone → specific receptor → cellular signaling cascade → biological effect

• No receptor → no response
• Membrane receptor → protein/peptide/catecholamine hormones
• Cytoplasmic receptor → steroid hormones
• Nuclear receptor → thyroid hormones
• Down-regulation → receptors ↓ → sensitivity ↓
• Up-regulation → receptors ↑ → sensitivity ↑
• Small hormone concentration can produce a large effect because the receptor-linked signaling cascade amplifies the response.

CONCEPTUAL EXAMPLES

• Protein/peptide hormone: hormone → membrane receptor → cellular signaling → response.
• Steroid hormone: hormone → cytoplasmic receptor → response.
• Thyroid hormone: hormone → nuclear receptor → response.
• High hormone exposure: receptor number ↓ → down-regulation → target becomes less sensitive.
• Up-regulation: receptor number/availability ↑ → target becomes more sensitive.

INTRACELLULAR SIGNALING AFTER HORMONE RECEPTOR ACTIVATION

• A hormone usually affects its target tissue by first forming a hormone–receptor complex.
• When the hormone binds, the receptor’s function changes.
• The activated receptor then starts the cellular processes that produce the hormone’s effects.
• Ion Channel–Linked Receptors
  • Almost all neurotransmitters, such as acetylcholine and norepinephrine, bind to receptors on the postsynaptic membrane.
  • Binding usually changes the receptor structure and causes an ion channel to open or close.
  • These channels may control the movement of:
    • Na⁺
    • K⁺
    • Ca²⁺
    • Other ions.
  • The resulting change in ion movement produces the effects in the postsynaptic cell.
  • Some hormones can also act through ion channel-linked receptors.
  • However, many hormones affect ion channels indirectly through G protein-coupled receptors or enzyme-linked receptors.
• G Protein–Coupled Hormone Receptors
  • Many hormones activate receptors that indirectly control target proteins such as enzymes and ion channels.
  • They do this through G proteins located in the cell membrane (Fig. 75.4).
  • Known G protein-coupled receptors have 7 transmembrane segments that pass in and out of the cell membrane.
  • The inside part of the receptor is connected to a G protein.
  • The G protein has 3 subunits: α, β, and γ.
  • When a hormone binds to the outside of the receptor, the receptor changes shape.
  • This activates the G protein and produces intracellular signals that can:
    • Open or close ion channels
    • Change enzyme activity
    • Activate gene transcription
• G proteins are named because they bind guanine nucleotides.
• In the inactive state, the α, β, and γ subunits are together.
• The α subunit contains GDP.
• When the hormone activates the receptor:
  • The G protein attaches to the activated receptor.
  • GDP is exchanged for GTP.
  • The α subunit separates from the βγ complex.
  • The activated α subunit interacts with other intracellular signaling proteins.
  • These proteins can change the activity of ion channels or enzymes such as adenylyl cyclase and phospholipase C.
  • These changes then alter cell function.
• The signal stops after the hormone is removed.
• The α subunit converts its bound GTP → GDP and becomes inactive.
• The α subunit then joins the β and γ subunits again.
• The inactive αβγ G protein complex is re-formed.
• Some hormones use inhibitory Gi proteins.
• Other hormones use stimulatory Gs proteins.
• Therefore, depending on the type of G protein involved, a hormone can increase or decrease intracellular enzyme activity.
• This G protein system allows different hormones to produce many different responses in different target tissues.

KEY CONCEPT

Hormone → receptor → intracellular signal → cell response

G protein pathway

Hormone binds receptor → receptor changes shape → GDP → GTP → α subunit separates → intracellular proteins activated → cell response

Stopping the signal:

GTP → GDP → α subunit becomes inactive → α + β + γ reunite

• Gs → stimulatory → increases enzyme activity
• Gi → inhibitory → decreases enzyme activity
• G protein signaling can control:
  • Ion channels
  • Enzymes
  • Gene transcription

CONCEPTUAL EXAMPLES

• Acetylcholine: receptor on postsynaptic membrane → ion channel opens/closes → ion movement → cell response.
• Hormone + Gs: receptor → Gs → intracellular enzyme activity increases.
• Hormone + Gi: receptor → Gi → intracellular enzyme activity decreases.
• Easy memory:
  GDP = OFF
  GTP = ON
  GTP → GDP = signal OFF

Figure 75.4 — ELI5: How a G Protein–Coupled Receptor (GPCR) Works

🧠 BIG IDEA FIRST

Think of a GPCR as a doorbell on the cell membrane.

• Hormone = person pressing the doorbell
• Receptor = doorbell
• G protein = messenger inside the house
• GDP = OFF signal
• GTP = ON signal
• Target enzyme = machine that produces the intracellular response

So the whole figure is:

Hormone binds receptor → G protein switches ON → α-subunit activates target enzyme → intracellular signal begins

1. 🧱 Cell membrane

The orange/pink double layer is the cell membrane.

It separates:

Outside

Extracellular fluid

from

Inside

Cytoplasm

The hormone is outside the cell.

The G protein and target enzyme are on the cytoplasmic side.

2. 🟢 Receptor — the “doorbell”

The green structure crossing the membrane is the:

G protein–coupled receptor (GPCR)

Notice that it passes through the membrane multiple times.

Most important concept:

The hormone cannot simply enter the cell.

Instead:

The hormone binds to the receptor on the outside of the membrane.

This changes the shape/function of the receptor.

That activated receptor then communicates with the G protein on the inside.3. 🔴 Hormone binds to receptor

The red circle labeled Hormone attaches to the receptor.

Think:

Before hormone:

Receptor = OFF

After hormone binds:

Receptor = ON

The receptor now activates the nearby G protein.

4. 🟣🟠🟢 What is the G protein?

The G protein has three subunits:

α (alpha)

β (beta)

γ (gamma)

Together:

α + β + γ = G protein

In the first part of the figure, all three are together.

5. 🔴 GDP means “OFF”

Look at the first G protein.

The α-subunit contains GDP.

GDP = OFF state

So:

α + GDP + β + γ

means:

🛑 G protein is inactive

This is why the figure labels it:

G protein (inactive)

6. 🔄 Hormone activates the receptor → GDP is replaced by GTP

This is the MOST IMPORTANT step.

When the hormone activates the receptor:

GDP leaves α

and

GTP binds α

So:

GDP OFF → GTP ON

Think of it like changing a battery switch:

GDP = OFF
GTP = ON

Now the G protein becomes:

G protein ACTIVE

7. 🟢 α-subunit separates from β + γ

Once GTP binds to α:

α-GTP separates from β and γ.

So instead of:

α + β + γ

we now have:

α-GTP ⟶ moves toward target protein

and

β + γ ⟶ remain together

Why does this matter?

Because α-GTP can now interact with another protein.

That other protein is the:

Target protein / enzyme

8. 🎯 Target protein — the next machine

The large yellow structure is the:

Target protein / enzyme

The activated α-GTP binds to it.

Think:

G protein = messenger
Target enzyme = machine

The messenger tells the machine:

“START!”

The enzyme then begins processes that produce intracellular signals.

9. ⚡ What happens after the target enzyme is activated?

The target enzyme can generate intracellular signaling molecules.

Depending on the type of G protein, this can lead to pathways involving things such as:

• cAMP
• IP₃
• DAG
• changes in Ca²⁺

These intracellular signals eventually produce the hormone’s effect.

Very important:

The hormone itself may be outside the cell, but its message is transmitted inside the cell.

🔥 The entire figure as a simple story

Imagine you are outside a house.

🧑 Hormone

You press the doorbell.

⬇️

🟢 GPCR

The doorbell receives the signal.

⬇️

🧬 G protein

The receptor activates the G protein.

⬇️

🔴 GDP leaves

The α-subunit loses its OFF signal.

⬇️

🟢 GTP binds

The α-subunit receives its ON signal.

⬇️

α-GTP separates

α separates from βγ.

⬇️

🎯 Target enzyme

α-GTP activates the target enzyme.

⬇️

⚡ Intracellular signals

The enzyme starts signaling inside the cell.

⬇️

🧠 Cellular response

The cell performs the hormone’s action.

⭐ The most important ON/OFF concept

GDP = OFF

GTP = ON

Memorize this:

GDP → inactive
GTP → active

This is one of the most important concepts in GPCR signaling.

🧩 Understand every label in the figure

Label	Easiest meaning
Hormone	External messenger
Receptor	Detects the hormone
Extracellular fluid	Outside of cell
Cytoplasm	Inside of cell
G protein	Intracellular messenger
α subunit	Main signaling subunit shown
β + γ subunits	Other two G-protein subunits
GDP	OFF form
GTP	ON form
Target protein/enzyme	Activated by G protein
Intracellular signals	Messages produced inside cell

🧠 10-SECOND EXAM REVISION

Inactive state:

GPCR + G protein (αβγ) + GDP

⬇️ Hormone binds

Activation:

GDP → GTP

⬇️

Separation:

α-GTP separates from βγ

⬇️

Action:

α-GTP → target enzyme

⬇️

Result:

Intracellular signaling → cellular response

🚨 One subtle but important point

The figure ends with α-GTP activating the target protein.

But the signal does not stay ON forever.

The α-subunit eventually hydrolyzes GTP → GDP.

Therefore:

GTP → GDP

and α becomes inactive again and can reassociate with βγ.

So the cycle is:

OFF → ON → OFF

GDP
⬇️ hormone/receptor activation
GTP
⬇️ target enzyme activation
GTP hydrolysis
⬇️
GDP

🔑 FINAL MASTER CONCEPT

Hormone outside the cell

↓

GPCR detects it

↓

GDP on α is replaced by GTP

↓

α-GTP becomes active

↓

α-GTP separates from βγ

↓

α-GTP activates target enzyme

↓

Intracellular signaling molecules are produced

↓

Cellular response

❤️ Remember it as:

“Hormone presses the receptor → receptor changes GDP to GTP → GTP turns G protein ON → α activates the enzyme → the message travels inside the cell.”

Figure 75.4 = GPCR is basically an OUTSIDE hormone signal being converted into an INSIDE cellular signal.