2 - Receptors Flashcards
The Three Stages of Cell Signaling
• Earl W. Sutherland - Nobel Prize in Physiology Medicine in 1971 ‘for his discoveries concerning the mechanisms of the action of hormones’
• Sutherland suggested that cells receiving signals went through three processes
1. Reception
2. Transduction
3. Response
Reception
Reception - detection by the cell of a signal (molecule) that usually originates from outside the cell
The signal is detected when signalling molecule interacts directly with a receptor on cell surface or inside the cell
This is normally referred to as receptor binding
Ligands
The signalling molecule is called a ligand i.e. it is a small molecule that binds to a larger one
- Ligand binding can lead to a change in the shape of a protein or aggregation of 2 or more receptors - enables receptor to interact with other molecules
- Receptor activation can then lead to further molecular changes inside the cell
Hydrophobic + hydrophilic messengers
Hydrophilic messengers (water soluble and often too large to pass through membrane) detected by membrane bound receptors Hydrophobic messengers can move through the lipid environment of the PM and so signal receptors can be located inside the cell
Receptors in the Plasma Membrane
• Most water-soluble signal molecules bind to specific sites on receptor proteins that span the plasma membrane
• There are three main types of membrane receptors
1. G protein-coupled receptors
2. Receptor tyrosine kinases
3. Ion channel receptors
Introduction to GPCRs
- G-protein-coupled receptor (GPCRs) are the largest family of cell-surface receptors (approx. 1000 encoded in human genome)
- A GPCR is a plasma membrane receptor -spans the membrane as seven α helices
G-protein
> Can bind guanine nucleotides - GTP (guanosine triphosphate) and GDP (guanosine diphosphate)
G protein – a molecular switch - ‘either on or off’
• When GDP is bound to the G-protein - G-protein is inactive – i.e. the switch is OFF
• When GTP is bound, the G-protein is activated - i.e. the switch is ON
How do GPCRs function?
- When signalling molecule binds to extracellular side of GCPR – receptor
activation - Activation – change in shape of the receptor – cytoplasmic side of GCPR binds to the inactive G protein
- Interaction between G protein and GCPR - GTP displaces GDP – G protein activation
- Activated G protein dissociates from GCPR – diffuses along membrane and binds to an enzyme
- This causes change in shape and activity of enzyme - enzyme activation leads to a cellular response
- Binding of signalling molecule (ligand) is reversible – binds and dissociates many times - ligand concentration determines how often signalling occurs
- Changes in enzyme and G protein are only temporary – because the G
protein also functions as a GTPase enzyme – i.e. it hydrolyses GTP to GDP - This returns G protein to inactive state and the G protein leaves the enzyme
- G protein now available for reuse – GTPase function allows the pathway to
shut down rapidly when the signalling molecule is no longer present
Examples of signalling pathways that use G-protein coupled receptors
Epinephrine or adrenaline - from adrenal gland - stimulates glycogen breakdown in liver and skeletal muscle during stress
Involved in bacterial diseases: Whooping cough (pertussis), Cholera, Botulism
Bacterial toxins in these cases interfere with normal G protein coupled receptor function
Also thought that up to 60% of all medicines used today exert their effects by influencing G protein pathways
Introduction to Receptor tyrosine kinases
- Receptor tyrosine kinases (RTKs) - also membrane bound receptors - differ from GPCRs - they have intrinsic enzyme activity
- Acts as an a tyrosine kinase - adds phosphate residues onto other proteins
- A RTK can trigger multiple signal transduction pathways at once
- Abnormal functioning of RTKs is associated with many types of cancers
Receptor tyrosine kinase activation
- Before ligand binds receptors exist as monomers. Each receptor monomer has an extracellular ligand binding site, amembrane spanning region and an intracellular tail containing multiple tyrosines
- Binding of ligand (e.g. growth factor) causes the 2 receptor monomers to associate with each other. Association forms a complex known as a dimer
- Dimerisation activates the tyrosine kinase region of EACH monomer. Each tyrosine kinase adds a phosphate from an ATP molecule to a tyrosine on the tail of the other monomer
- The receptor is fully activated and recognised by specific relay proteins. Relay protein binds to specific phosphorylated tyrosine - structural change activates the relay protein. Each activated protein triggers a transduction pathway
Receptor Tyrosine Kinases (RTKs)
animal Growth Factors, Involved in cell growth and division
Abnormal RTK function associated with a number of cancers
Some breast cancer patients – excessive levels of a RTK called HER2 (Human Epidermal growth factor Receptor 2) – poor prognosis
Herceptin – approved for the treatment of early-stage breast cancer treatment – binds to HER2 on cells and inhibits their growth and division
Herceptin – monoclonal antibody that binds to receptor
Introduction to Ligand-gated ion channels
- A ligand-gated ion channel receptor acts as a gate - structure creates a pore in the plasma membrane that can open or close in response to an extracellular chemical messenger
- Hence the name is derived from the signalling molecule (the ligand) opening (the gate) on the entrance (the pore) into the cell
- When a signal molecule (ligand) binds to the receptor - the gate allows specific ions, such as Na+ or Ca2+, through a channel in the receptor
How do ligand gated ion channels function?
- Gate is closed until a ligand binds to the receptor
- Ligand binds to receptor – gate opens and specific ions can flow through the channel into the cell – this rapidly changes the intracellular concentration of that ion – causes cellular response
- When ligand dissociates from the receptor the gate closes and ions can no longer enter the cell
Examples of Ligand-gated ion channels
Very important in the nervous system – e.g. neurotransmitter molecules released at a synapse between 2 nerve cells
Neurotransmitter bind as ligands to ion channels on receiving cell – causes channels to open
Ions flow in (or out) triggering an electrical signal that propagates down the length of the receiving cell
Some gated ion-channels are controlled by electrical signals instead of ligands – voltage-gated ion channels crucial to functioning of the nervous system
