Receptors and signalling

Question 1

How to cells communicate?

Answer 1

• All parts of an organism must work in a coordinated fashion
• This requires long- and short-range communication between cells
• Cells must maintain their overall membrane integrity to operate
• Information must cross the cell membrane
• Small signals must be amplified into large changes

Question 2

What do neurons and nerve cells do?

Answer 2

• Send messages through electrical pulses along their length
• The message must be passed between cells – there is a gap of ca. 10 nm between cells

Question 3

What does the communication between nerve cells involve?

Answer 3

The communication between nerve cells involves rapid release and diffusion of a neurotransmitter (NT) to another cell where it binds to a receptor resulting in a change in the properties of the postsynaptic cell

Question 4

What are neurotransmitters?

Answer 4

Neurotransmitters are chemicals secreted from the presynaptic membrane.

Question 5

What are electrical synapses?

Answer 5

ions flow directly from one neurone to another via gap-junctions.

Question 6

What is another way cells can communicate?

Answer 6

Through chemical messages: hormone

Question 7

When are hormones used for communication?

Answer 7

Hormones circulate in larger regions than synapses, from the local vicinity up to entire body circulation

Question 8

Membrane proteins associate with the lipid bilayer…

Answer 8

• Their hydrophobic regions interact with the hydrophobic tails of the lipid molecules in the bilayer, where they are sequestered away from water.
• Their hydrophilic regions are exposed to water on either side of the membrane

Question 9

Most transmembrane proteins extend across the bilyaer as either…

Answer 9

• a single α helix (amphipathic α helix)
• as multiple α helices
• as a rolled-up β sheet (a β barrel)

Question 10

Receptor proteins are membrane proteins…

Answer 10

• Chemical messenger (neurotransmitter/hormone = ligand) binds to receptor
• This induces a change in the protein conformation affecting the region inside the cell
• The changed conformation activates the intracellular domain
• After sending the message many times, the chemical messenger leaves

Question 11

How do neurones propagate pulses?

Answer 11

Neurons propagate pulses by letting ions flow in/out

Question 12

What won’t usually pass through a cell membrane?

Answer 12

Ions (polar!) would not usually pass through a cell membrane – use channel proteins

Question 13

What do most channel proteins have?

Answer 13

Most channel proteins necessarily have narrow, highly selective pores that can open and close.

Question 14

What type of transport happens in neurone propagation?

Answer 14

• Transport is ‘downhill’ – passive, along concentration gradient
• Transport is extremely fast – ~100s million ions per second per channel

Question 15

What are the different types of ion channel gating?

Answer 15

• Voltage-gated
• Ligand-gated extracellular)
• Ligand-gated (intracellular)

Question 16

What do toxins and venoms do?

Answer 16

Toxins and venoms which block ion channels shut down the organism’s nervous system, which is why a snake or spider bite is so deadly and fast-acting.

Question 17

How do 30% of drugs act?

Answer 17

By binding G-protein coupled receptors (GPCRs)

Question 18

How are GCPRs activated?

Answer 18

By neurotransmitters and peptides hormones binding

Question 19

What does ligand binding result in?

Answer 19

Ligand binding results in activation or deactivation of certain membrane-bound enzymes called G-protein

Question 20

G proteins are…

Answer 20

membrane-bound and comprised of three subunits, alpha, beta, gamma

Question 21

What does the alpha unit bind?

Answer 21

Guanyl nucleotides and hosts GDP in its resting state

Question 22

Activation by the GCPR eventually results in…

Answer 22

• Activation by the GCPR eventually results in the cleavage of the alpha unit from the gamma beta unit
• This can happen many times during the binding of one ligand which is also known as signal amplification

Question 23

What happens in steps 1 & 2 of G-protein signal transduction?

Answer 23

The ligand binds G protein hosting GDP in an alpha subunit.

Question 24

What happens in step 3 of G-protein signal transduction?

Answer 24

Binding changes the conformation of the G-protein, releasing GDP.

Question 25

What happens in step 4 of G-protein signal transduction?

Answer 25

A pocket is created which binds GTP

Question 26

What happens in step 5 of G-protein signal transduction?

Answer 26

Binding of GTP causes another conformational change

Question 27

What happens in step 6 of G-protein signal transduction?

Answer 27

This results in the alpha subunit departing separately

Question 28

What happens in step 7 of G-protein signal transduction

Answer 28

The α subunit with GTP diffuses along the membrane to adenylate cyclase which is then activated to catalyse ATP –> cAMP

Question 29

What happens in step 8 of G-protein signal transduction?

Answer 29

The α subunit has intrinsic GTPase activity, resulting in GTP –? GDP after some time

Question 30

What happens in step 9 of G-protein signal transduction?

Answer 30

This reverses binding and deactivates adenylate cyclase.

Question 31

What happens in step 1 of phosphorylation?

Answer 31

cAMP activates protein kinase A

Question 32

What happens in step 2 of phosphorylation?

Answer 32

Protein kinase A phosphorylates other specific proteins

Question 33

What happens in step 3 of phosphorylation?

Answer 33

Phosphorylation changes their conformations and activates them in turn

Question 34

What happens in step 4 of phosphorylation?

Answer 34

Each step can have multiple turnovers = huge signal amplification

Question 35

Binding of the ligand on the extracellular side…

Answer 35

• Binding of the ligand on the extracellular side results in direct activation of the protein as a kinase on the intracellular side
• Often binding results in some level of dimerization which turns on activity

Question 36

What is EGF?

Answer 36

Bivalent peptide hormone

Question 37

What does EGF do?

Answer 37

• EGF is a bivalent peptide hormone
• This results in receptor dimerization
• Each half of the receptor catalyses tyrosine phosphorylation on the other half

Question 38

Insulin and GH are both…

Answer 38

Insulin and GH are both peptide hormones

Question 39

What do signal transduction pathways do?

Answer 39

This scheme exemplifies signal transduction, using EGFR as a starting point.

Question 40

What happens once EGFR is phosphorlayed

Answer 40

Once EGFR is phosphorylated, it can interact with a whole range of other proteins, activating them to interact with further other kinases, etc.

Question 41

What determines the expression levels in the cells?

Answer 41

These are determined by transcription factors, which are themselves often at the end of the signalling cascades.

Question 42

What does the signal transduction pathway depend on?

Answer 42

The exact balance of this network will depend on expression levels within the cell

Question 43

What is an agonist?

Answer 43

A ligand that binds to, and provokes a signal from a receptor via conformational changes to produce the active state. Typically binds in a similar way to the natural ligand.

Question 44

What is an antagonist?

Answer 44

A ligand that binds to a receptor and induces no signal. Blocks agonist binding, and hinders conformational switch to active state.

Question 45

What is a partial agonist?

Answer 45

Binds and provokes a signal, but diminished compared to a full agonist. Binding is suboptimal and conformational switch may not fully engage.

Question 46

What is an inverse agonist?

Answer 46

Removes any base-level activity the receptor had in absence of the ligand