topic 12 - receptors and signalling Flashcards
how do 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 are neurons and neurotransmitters?
Neurons – nerve cells – send messages through electrical pulses along their length – like wires.
It is rare that one nerve cell is long enough to reach its target.
The message must be passed between cells – there is a gap of ca. 10 nm between cells.
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.
Neurotransmitters are chemicals secreted from the presynaptic membrane. Electrical synapses - ions flow directly from one neurone to another via gap-junctions.
what are hormones?
Other cells also communicate through chemical messages: hormones.
Hormones circulate in larger regions than synapses, from the local vicinity up to entire body circulation
Hormones have a wide range of structures.
what are general receptor principles?
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 bilayer as either:
- a single α helix (amphipathic α helix)
- as multiple α helices
- as a rolled-up β sheet (a β barrel).
general receptor principles pt 2
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.
what are Ion channel receptors?
Neurons propagate pulses by letting ions flow in/out.
Ions (polar!) would not usually pass through a cell membrane – use channel proteins
Most channel proteins necessarily have narrow, highly selective pores that can open and close.
Transport is ‘downhill’ – passive, along concentration gradient
Transport is extremely fast – ~100s million ions per second per channel.
what is Ion channel gating?
The gating of ion channels by different kinds of stimuli.
- Voltage gated
- Ligand gated (extracellular ligand)
- Ligand gated (intracellular ligand).
Ligands can be neurotransmitters, toxins & venoms such as tetrodotoxin.
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.
what are the Mechanics of Ion channel gating?
Ion channels are made of five similar proteins
Circles = ligand binding sites.
Each protein has four transmembrane domains
TM2 is always in the centre.
what are G-protein couples receptors? (GPCR’s)
30% of drugs act by binding GPCRs
Includes the muscarinic, adrenergic, and opioid receptors – nervous system
Activated by neurotransmitters (acetyl choline, dopamine, histamine…) and peptide hormones (enkephalins, endorphins)
Ligand binding results in activation or deactivation of certain membrane-bound enzymes called G-proteins.
what are G-protein couples receptors? (GPCR’s) pt 2
G-proteins are membrane bound and comprise of three subunits: α, β, and γ
The α unit binds guanyl nucleotides, and hosts GDP in its resting state.
Activation by the GPCR eventually results in cleavage of the α unit from the βγ unit
This can happen many times during binding of one ligand – signal amplification.
what is G-protein signal transduction?
1-2 The ligand binds G-protein hosting GDP in the α subunit.
3 Binding changes the conformation of the G-protein, releasing GDP.
4 … and creating a pocket which binds GTP.
5 Binding of GTP causes another conformational change
6 This results in the α subunit departing separately.
refer to slide 14 of lecture 12 receptors and signalling for the image^.
what is phosphorylation?
- cAMP activates Protein kinase A.
- Protein kinase A phosphorylates other specific proteins
- Phosphorylation changes their conformations and activates them in turn
- Each step can have multiple turnovers = huge signal amplification
what are Kinase receptors?
Kinase receptors are simpler than GPCRs:
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.
Epidermal growth factor receptor (EGFR)
in complex with the epidermal growth factor (EGF)
EGF is a bivalent peptide hormone. This results in receptor dimerization. Each half of the receptor catalyses tyrosine phosphorylation on the other half.
what are the signal transduction pathways?
This scheme exemplifies signal transduction, using EGFR as a starting point.
Once EGFR is phosphorylated, it can interact with a whole range of other proteins, activating them to interact with further other kinases, etc.
The exact balance of this network will depend on expression levels within the cell
These are determined by transcription factors, which are themselves often at the end of the signalling cascades.
Each protein can activate many others, so amplification is built in at every step.
what are agonists, antagonists and inverse agonists?
Drugs can interact with receptors in four ways:
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.
Antagonist - A ligand that binds to a receptor and induces no signal. Blocks agonist binding, and hinders conformational switch to active state.
Partial agonist - Binds and provokes a signal, but diminished compared to a full agonist. Binding is suboptimal and conformational switch may not fully engage.
Inverse agonist - Removes any base-level activity the receptor had in absence of the ligand
