L13: Intracellular Signalling Flashcards
What order does cell signalling work in?
- Signal (via primary messenger/ ligand)
- Receptor (receptor protein)
- Transduction (transduction proteins)
- Effector (secondary messenger signalling cascade)
- Response
Receptors can either be what?
- Cell surface: hydrophillic signalling molecules cannot cross membrane and must bind to cell surface receptors e.g. cytokines, neurotransmitters
- Intracellular: small hydrophobic signalling molecules can cross membrane and bind to intracellular receptors e.g. steroid hormones
Name sub types of cell surface receptors (CSFs)
Ligand gated ion channels (nicotinic, ionotropic), GPCRs (muscarininc, metabotropic) and kinase-linked (cyotokine) receptors
Briefly state the structure of GPCRs
There are 3 exoloops in the extracellular and 4 cytoloops in intracellular matric
Signal must be large and specific. True or false?
False, it must be small and specific
Name and explain the different types of signals
- Endocrine: uses vascular system
- Paracrine: made in nearby cell
- Autocrine: made in its own cell & is its own target
How may ion-channel linked receptors neurotransmitters be removed from the synapse?
Via transporter proteins
What happens when ion-channel linked receptors neurotransmitters are removed from the synapse?
They move back into the presynaptic cell, to be repackaged into vesicles or broken down by enzymes
How many membrane spanning domains does GPCR have?
7 aka serpentine receptors
Explain the process of GPCR
- Ligands bind to receptor→ conformational change which is passed onto the G-protein
- Once G-protein is activated alpha loses GDP and is phosphorylated to GTP & alpha dissociates from beta and gamma
- beta-gamma subunit can go off and signal but need to remain membrane bound, as there’s more chances of coming into contact with target
- Phosphate from GTP is transferred to target protein, activating it
- After alpha subunit is deactivated it loses GTP and rebinds to GDP, so it can associate with beta-gamma to reform inactive G protein
What is the typical nature of the target protein?
Often an enzyme, resulting in the productoin of a secondary messenger that activates the rest of the pathway
Give examples of secondary messengers and what they trigger
- Inositol phosphodates and diacylglycerol (remains in membrane) activates protein kinase C and Ca stores
- CAMP (released into cytoplasm) activates protein kinase A
- cGMP (released into cytoplasm) activates protein kinase G
Explain how enzyme linked receptors work
- Ligand enters and binds, forming cross links
- Intracellular part of receptor contains tyrosine kinase domains, which are activated by phopshorylation
- These domains go onto to phosphorylate other proteins inside the cell and then signalling pathways
What do phosphorylated tyrosine residues provide for proteins?
Docking sites
- for each tyrosine there’s a motif of AAs inside that will be recognised by specific proteins
- allows different parts of signalling pathways to come together and interact in a border
What is ‘cross-talk’
When there is overlpa between many signalling pathways
- common secondary messengers are shared by different pathways and some signalling proteins are shared by different proteins
How can the correct pathway be ensured to be activated?
Via affinity and trigger levels
- this allows fine tuning of response but may also result in the wrong response
How can a signal be turned off?
- removal/ inactivation of signal or receptor
- inactivation of activated signalling proteins (via GTP hydrolysis or dephosphorylation)
- degradation/ removal of secondary messengers
Give 2 examples of GPCRs and their mechanisms
- Rhodopsin: agonist, fast activation (<1s), slow deactivation (half life ~6m)
- beta 2 Adrenergic: diffusible agonists, activation is slow (half life ~3m), deactivation is faster (~30s)
How can signal targetting occur?
Through
- more than one messenger
- production of different primary messengers
- expresssion of different receptor subtypes in different cells
- expression of different downstream components in different cells
- intracellular targeting/ localistion of signl
What happens when parts of the signalling pathway need to return to starting state?
- receptors retruned to cell membrane
- other proteins removed from membrane e.g. GLUT4
- messengers re-stocked e.g. PIP2
What is a key factor (conceptually) in signalling?
Control
- over activation, deactivation, message in cells and process
- loss of control can lead to disease
