Cell Signalling Flashcards
What are the main stages of cell signaling?
Reception: requires extracellular signal to be recognised e.g. by a receptor.
Transduction: signalling molecule alters the receptor and initiates transduction, a pathway of steps involving relay molecules.
Response: a specific cellular response is triggered.
Describe specificity of signalling
Most signalling systems are highly specific. e.g. one receptor only recognises one (or a few) specific ligands.
Not all cells possess all receptors and/or all intracellular targets.
Insulin might affect liver/muscle/fat cells but does not affect epithelial cells (absence of receptor).
Adrenaline binds to erythrocytes but doesn’t alter glycogen metabolism like it does in hepatocytes despite both cells having the receptor (absence of intracellular target).
Describe sensitivity of signalling
Most signalling systems are highly sensitive.
High affinity binding to receptors.
Receptor proteins can bind ligands at very low concentrations (picomolar concentrations 10-12 moles/litre).
Co-operative nature of ligand binding.
Ligand binding induced structural/conformational change in receptor, primes for subsequent ligand binding.
Cascade nature of signalling pathway causes amplification.
Small amount of ligand can have a dramatic effect on a cell.
Describe the signalling cascade
Each enzyme can activate many molecules of a second enzyme the effect is amplified at each stage, with the result that a single hormone molecule may alter the activity of tens of thousands of protein molecules within a cell.
What are receptors and their general structure
Proteins responsible for recognition and binding of specific molecules.
Mainly glycoproteins.
Typically integral membrane proteins with ligand binding site on extracellular face.
Ligand binding is reversible (weak non-covalent bonds).
Binding of ligand causes conformational change in receptor, resulting in a change within the target cell.
An extracellular ligand binding domain.
A hydrophobic domain, which extends through the membrane.
An intracellular domain, which generally transmits a signal.
What are the main receptor types?
G-protein coupled receptors.
Ion channel receptors.
Tyrosine kinase receptors.
Describe GPCRs
serpentine receptors. Ligand binds to extracellular domain (amino terminal).
7 transmembrane (alpha-helix) spanning domains. C-terminal cytosolic loop interacts with G-protein.
G-proteins are small proteins on the cytoplasmic face of membrane. Binds guanine nucleotides (GDP and GTP). Acts as an on/off switch. Have intrinsic GTPase activity (can hydrolyse GTP).
Binding of a ligand to a GPCR activates the G-protein to swap or exchange GDP for GTP.
When the triphosphate nucleotide (GTP) is bound, the G-protein is said to be active or “switched on”.
The active G-protein then dissociates from the receptor and activates an effector such as an enzyme or ion channel.
Having done this job, the G-protein is then “switched off” by hydrolysing the GTP back to GDP, releasing inorganic phosphate in the process.
Describe ion channel receptors
Act as pores to allow passage of ions such as Na+, K+, Cl-, and Ca2+.
An ion channel is generally selective for the type of ion it allows through i.e. positive or negative ions, but not both.
Movement of ions from one side of a membrane to the other causes a change in the distribution of charge.
This influences change within the cell.
Found in excitable cells e.g. neurons and muscle cells (myocytes).
Two types of ion channel receptors:
Ligand gated ion channels.
Voltage gated ion channels
Describe ligand gated ion channels
Open in response to binding of a ligand (opposite can also be true).
Ligand binding to receptor causes the ion channel to change conformation.
This opens a pore in the membrane allowing passage of ions across the lipid bilayer.
Dissociation of the ligand causes the channel to close again.
Describe tyrosine kinase receptors
Intrinsic tyrosine kinase activity.
Activation leads to autophosphorylation of certain tyrosine residues.
Autophosphorylation further activates receptor to carry out its effect within the target cell.
Phosphorylated tyrosine can transmit signal to other molecules in the cell.
One of the best characterised tyrosine kinase receptors is the insulin receptor:
Insulin binds alpha subunits (receptors).
Causes conformation change.
Results in autophosphorylation of tyrosine residues in C-terminus of beta subunits.
Autophosphorylation causes enhanced activity of tyrosine kinase domain.
Other target proteins phosphorylated to mediate intracellular effects of insulin.
Describe receptor desensitisation
Sensitivity of ligand/receptor interactions can be altered through desensitisation.
If concentration of a ligand is persistently high, cell adapts by activating a feedback mechanism that switches off the signal.
This feedback mechanism (desensitisation) can involve:
- switching off the receptor
- removing the receptor
Describe intracellular receptors
Steroid hormones cause changes in cell activity through intracellular receptors.
Steroid hormones are lipophilic and can easily pass through the cell membrane as it is primarily a lipid bilayer.
These hormones regulate cell activity by binding to, and interacting with DNA.
Result is that DNA transcription and ultimately protein translation is affected.
