JC2: Signalling, receptors, and pharmacology (2)

Question 1

What are hormones?

Answer 1

Molecules that are released from one site for action at another

Question 2

What do cells require to respond to extracellular signalling molecules? Why?

Answer 2

The appropriate receptor

This ensures the extracellular signalling molecules are in the correct place and performing the correct action

Question 3

Where are the majority of cellular receptors found? Why?

Answer 3

At the cell surface because the majority of extracellular signalling molecules do not readily cross the plasma membrane

Question 4

What are the four receptor subtypes? Give an example of each.

Answer 4

1. Ligand-gated ion channels, e.g. nicotinic acetylcholine receptors
2. Receptors with intrinsic enzymatic acticivty, e.g. receptor tyrosine kinases (e.g. insulin receptor)
3. G protein-coupled receptors, e.g. muscarinic acetylcholine receptors
4. Intracellular receptors, e.g. steroid receptors, thyroid hormone receptors

Question 5

How do ligand-gated ion channels work?

Answer 5

The ligand binds and causes a conformational change of the ion channel, so ions can move into or out of the cell

Question 6

How does an insulin receptor work?

Answer 6

Ligand binding activates an enzyme activity that phosphorylates the receptor and other substrates

This causes the receptor to dimerise

This is known as autoactivation

Question 7

How do intracellular (nuclear) receptors work?

Answer 7

The ligand binds to the receptor in the cytoplasm, causing dissociation to a dimer

The dimer moves from the cytoplasm to the nucelus and binds directly to points on the DNA

This regulates gene transcription

Question 8

What percentage of available prescription drugs exert their therapeutic effects directly or indirectly at GPCRs?

Answer 8

Approx. 30%

Question 9

What is the difference between an agonist and an antagonist?

Answer 9

Agonists bind to the receptor and activate it

Antagonists bind to the receptor but to not activate it

Question 10

What do antagonists prevent?

Answer 10

Endogenous activation of receptor

Question 11

What do sensory GPCRs sense?

Answer 11

Light, odours, tastes

Question 12

What can GPCRs respond to?

Answer 12

• Ions
• Neurotransmitters
• Peptide and non-peptide hormones
• Large glycoproteins

Question 13

What is the common structure of GPCRs?

Answer 13

• Single polypeptide chain
• 7 transmembrane-spanning regions
• Extraceulluar N-terminal
• Intracellular C-terminal

Question 14

What are the two different regions of GPCRs that can be responsible for ligand binding?

Answer 14

1. 2-3 of the transmembrane domains
2. N-terminal region and other extracellular domains

Question 15

How do GPCRs respond to ligands?

Answer 15

By changing conformation

Question 16

What does the G in ‘G protien’ stand for?

Answer 16

Guanine nucleotide-binding

Question 17

What must an activated GPCR interact with?

Answer 17

A G protein

Question 19

What are the subunits of G proteins?

Answer 19

α, β and γ

Question 20

Why is a G protein heterotrimeric?

Answer 20

It has three different subunits

Question 21

How do GPCRs alter cellular activity?

Answer 21

The G protein binds and causes the α subunit to release GDP and replace with GTP (GDP-for-GTP exchange)

The α-βγ complex immediately dissociated (into α-GTP and βγ) and each can then interact with effector proteins

Question 22

Describe the process of termination of G protein signalling

Answer 22

The α-GTP and/or βγ interaction with effectors lasts until the α subunit GTPase activity hydrolyses GTP back to GDP

α-GDP and βγ subunits then reform an inactive heterotrimeric complex

Question 23

How many different α, β, and γ proteins are encoded by the human genome?

How many possible Gα-βγ combinations are there?

Answer 23

20 Gα, 5 Gβ, 12+ Gγ

>1000 possible Gα-βγ combinations

Question 24

What governs receptor-G protein selection?

Answer 24

Activated GPCRs preferentially interact with specific types of G protein, with the Gα subunit being the primary determinant

Gα subunits and Gβγ subunits interact with specific effector proteins

Question 25

Complete this table.

Answer 25