Receptors and signalling Flashcards
How to cells communicate?
- 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
What do neurons and nerve cells do?
- 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
What does the communication between nerve cells involve?
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
What are neurotransmitters?
Neurotransmitters are chemicals secreted from the presynaptic membrane.
What are electrical synapses?
ions flow directly from one neurone to another via gap-junctions.
What is another way cells can communicate?
Through chemical messages: hormone
When are hormones used for communication?
Hormones circulate in larger regions than synapses, from the local vicinity up to entire body circulation
Membrane proteins associate with the lipid bilayer…
- 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
Most transmembrane proteins extend across the bilyaer as either…
- a single α helix (amphipathic α helix)
- as multiple α helices
- as a rolled-up β sheet (a β barrel)
Receptor proteins are membrane proteins…
- 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
How do neurones propagate pulses?
Neurons propagate pulses by letting ions flow in/out
What won’t usually pass through a cell membrane?
Ions (polar!) would not usually pass through a cell membrane – use channel proteins
What do most channel proteins have?
Most channel proteins necessarily have narrow, highly selective pores that can open and close.
What type of transport happens in neurone propagation?
- Transport is ‘downhill’ – passive, along concentration gradient
- Transport is extremely fast – ~100s million ions per second per channel
What are the different types of ion channel gating?
- Voltage-gated
- Ligand-gated extracellular)
- Ligand-gated (intracellular)
What do toxins and venoms do?
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.
How do 30% of drugs act?
By binding G-protein coupled receptors (GPCRs)
How are GCPRs activated?
By neurotransmitters and peptides hormones binding
What does ligand binding result in?
Ligand binding results in activation or deactivation of certain membrane-bound enzymes called G-protein
G proteins are…
membrane-bound and comprised of three subunits, alpha, beta, gamma
What does the alpha unit bind?
Guanyl nucleotides and hosts GDP in its resting state
Activation by the GCPR eventually results in…
- 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
What happens in steps 1 & 2 of G-protein signal transduction?
The ligand binds G protein hosting GDP in an alpha subunit.
What happens in step 3 of G-protein signal transduction?
Binding changes the conformation of the G-protein, releasing GDP.
What happens in step 4 of G-protein signal transduction?
A pocket is created which binds GTP
What happens in step 5 of G-protein signal transduction?
Binding of GTP causes another conformational change
What happens in step 6 of G-protein signal transduction?
This results in the alpha subunit departing separately
What happens in step 7 of G-protein signal transduction
The α subunit with GTP diffuses along the membrane to adenylate cyclase which is then activated to catalyse ATP –> cAMP
What happens in step 8 of G-protein signal transduction?
The α subunit has intrinsic GTPase activity, resulting in GTP –? GDP after some time
What happens in step 9 of G-protein signal transduction?
This reverses binding and deactivates adenylate cyclase.
What happens in step 1 of phosphorylation?
cAMP activates protein kinase A
What happens in step 2 of phosphorylation?
Protein kinase A phosphorylates other specific proteins
What happens in step 3 of phosphorylation?
Phosphorylation changes their conformations and activates them in turn
What happens in step 4 of phosphorylation?
Each step can have multiple turnovers = huge signal amplification
Binding of the ligand on the extracellular side…
- 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
What is EGF?
Bivalent peptide hormone
What does EGF do?
- EGF is a bivalent peptide hormone
- This results in receptor dimerization
- Each half of the receptor catalyses tyrosine phosphorylation on the other half
Insulin and GH are both…
Insulin and GH are both peptide hormones
What do signal transduction pathways do?
This scheme exemplifies signal transduction, using EGFR as a starting point.
What happens once EGFR is phosphorlayed
Once EGFR is phosphorylated, it can interact with a whole range of other proteins, activating them to interact with further other kinases, etc.
What determines the expression levels in the cells?
These are determined by transcription factors, which are themselves often at the end of the signalling cascades.
What does the signal transduction pathway depend on?
The exact balance of this network will depend on expression levels within the cell
What is an agonist?
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.
What is an antagonist?
A ligand that binds to a receptor and induces no signal. Blocks agonist binding, and hinders conformational switch to active state.
What is a partial agonist?
Binds and provokes a signal, but diminished compared to a full agonist. Binding is suboptimal and conformational switch may not fully engage.
What is an inverse agonist?
Removes any base-level activity the receptor had in absence of the ligand
