Types and Function of Receptors

Definition of Pharmacology

The science of drugs and how they act in a biological system

What are the four main protein drug targets?

• Receptors

• Ion channels

• Enzymes

• Transporters

What are ion channels?

Membrane proteins that open in response to a cue and allow specific ions to move down their concentration gradient.

Ion Channel Blockers

• Blocks the ion channel

• Prevents ion movement

Ion Channel Modulators

• Increases/decreases chance of the ion channel opening

What are enzymes?

Biological catalysts that mediate biochemical reactions.

Enzyme inhibitors

• Prevents activity

False substrates

• Abnormal metabolite produced

Prodrug

• Activation of drug molecule

What are transporters?

• Proteins that carry substances across membranes

• Transporters can move substances against a gradient (active transport).

How are transporters different from ion channels?

Transporters are not pores, they are not open to both sides of the membrane at once. They bind to the solute and undergo a conformational change to move it across

Transporter inhibitor

• Transporter inhibitors block transport

Transporter false substrate

• False substrates leads to an abnormal compound accumulating

What is a receptor?

A protein (usually on the cell surface) that responds to exogenous cue and relay signal into a cell to produce a response.

What do receptors allow for?

Receptors allows fine tuning of physiological function

Definition of Ligand

Something that binds to a receptor

Definition of Agonist

Something that binds and induces a response

Definition of Antagonist

Something that binds and produces no response

What is a second messenger?

An intracellular signalling molecule that relays the signal from receptor to effector.

What is signal transduction?

A sequence of events/secondary messengers that leads to a biological response.

What happens when a ligand binds to a receptor?

1. A ligand binds to receptor

2. This binding causes conformational change of receptor protein

3. Conformational change results in cellular effect, for example:
   - Opening of channel
   - Activation of linked enzyme
   - Recruitment of effector protein
   - Intracellular transport

What are the 4 main families of receptors?

• Ligand gated ion channels

• G protein-coupled receptors (GPCRs)

• Kinase-linked receptors

• Nuclear receptors

What are Ligand-Gated Ion Channels?

Receptors that open an ion channel directly when a ligand binds.

What’s the difference between ligand gated ion channels and ion channels in general?

The channel opens only when a ligand binds. Ion channels are always open.

What is a kinase?

An enzyme that uses ATP to phosphorylate targets, acting as an on/off switch.

Are kinases second messengers?

Yes

How are kinase-linked receptors activated?

1. There’s a receptor in 2 halves in the membrane (monomer)

2. Ligand-receptor engagement brings the 2 receptor proteins (the 2 halves) together in the membrane (dimer)

3. This activates the kinase-linked receptor

4. The activation initiates a downstream cascade and biological response

What does EGFR stand for?

Epidermal growth factor receptor

Why is EGFR important clinically?

• EGFR are a type of kinase-linked receptor

• Some types of lung cancer express more EGFR proteins, leading to more growth

• These cancers are therefore susceptible to drugs that target EGFR

What defines a GPCR?

• A receptor with 7 transmembrane domains and is coupled to G protein

• Ligand binding activates G protein which interacts with effector

• Different GPCRs coupled to different G proteins. These elicit different effects

How are GPCRs activated?

Ligand binding activates the G-protein, which interacts with the effector

Are different GPCRs coupled to different G proteins?

Yes, and different G proteins have different effects

What are nuclear receptors?

Intracellular receptors that regulate gene expression.

How are nuclear receptors activated?

1. The ligand enters the cell and binds to the receptor in the cytoplasm.

2. This forms a ligand-receptor complex

3. The ligand-receptor complex then moves into the nucleus and acts on gene expression

What does “signal – action – response” mean?

Ligand binding → receptor activation → intracellular signalling → biological effect.

Match receptor type to activation mechanism.

• Ligand-gated ion channel

• GPCR

• Kinase-linked receptor

• Nuclear receptor

/

→ G-protein activation

→ gene expression

→ phosphorylation cascade

→ channel opening

• Ligand-gated ion channel → channel opening

• GPCR → G-protein activation

• Kinase-linked receptor → phosphorylation cascade

• Nuclear receptor → gene expression