Week 6 (cell Signalling) Flashcards
Describe cellular communication
- no cell exists in isolation
- signals must be received and processed from the environment and from other cells
- signals are generally transmitted across the environment in the form of soluble molecules
- these molecules must be detected and appropriate responses produced
What are the different modes for the cell to receive stimuli (cell signalling)?
- Contact dependent
- Paracrine
- Synaptic
- Endocrine
- Autocrine
What is autocrine signalling?
Self signalling
Why are receptors on the cell membranes necessary?
- membrane is impermeable to large soluble molecules
- some are transported across the membrane
- others are detected outside of the cell nd a signs, transmitted into the cell
- this is the role of receptors
What is a ligand?
A molecule that binds to a receptor
Describe the relationship between receptors and ligands
- Some receptors have one ligand whereas others have many
- Different ligands produce different responses at the same receptor e.g agonist/antagonist
Receptors detect a vast array of signals:
Dissolved gases Amino acids Peptides/proteins Retinoids Fatty acids Nucleotides
describe the plasma membrane in relation to being an interaction surface with the surrounding of a cell
- receptors are generally integral (transmembrane) proteins
- the extracellular region detects ligands
- the intracellular region interacts with effectors
Where can receptors be located?
- receptors can be either on the cell surface (peripheral proteins) or intracellular (integral proteins)
How do receptors modify cellular responses?
Signalling cascades
What 3 main domains do receptors have?
Extracellular domain
Transmembrane domain
Intracellular domain
What are intracellular mediators?
Proteins that transmit the signal from the receptor to the effector enzymes
What are effector enzymes
Bring about changes in cell resulting in, and affected by the production of second messenger
For a receptor to be able to detect a signal it must contain?
- contains at least one binding site for a ligand
What are the 4 main types of receptors?
- Ligand gated ion channels (cell surface receptor)
- G protein coupled receptors (cell surface receptor)
- Receptor tyrosine kinase (cell surface receptor)
- Intracellular receptor
What are receptor tyrosine kinases?
- transmembrane proteins
- bind extracellular ligand (comes as a dimer or has 2 binding sites)
- the dimer (consists of two of the same proteins that come together)
- extracellular ligand binding domain
- intracellular kinase domain (possesses enzymatic activity- can phosphorylate proteins)
What is the function of Kinases?
- kinases add phosphate group to amino acids in proteins using ATP
- kinases phosphorylate proteins
Explain phosphorylation in signalling
- often used as a signalling mediator
- phosphorylation can cause either protein activation or inactivation
- phosphorylation is reverses by phosphatases
Explain receptor tyrosine kinases (RTK)
- RTK phosphorylates tyrosine residues on a variety of target proteins in response to ligand binding
- ligand binding site formed from both molecules of the dimer
- the two molecules come together and trap the ligand
- this results in two intracellular domains coming together
What does phosphorylation do in receptor tyrosine kinases?
-Changes the properties of the kinase domain and allows it to interact with other molecules because phosphorylation sites are recognised by cyosolic proteins and bind to them thus conveying the signal further
How can RTK use monomeric GTPases as molecular switches?
- The GTPase protein is “off” when GDP is bound
- Then it receives a signal and GTP replaces GDP
- GTPase protein now bound to GTP and is now “on” in its activated state allowing it to pass the signal on
- GTP is hydrolysed by the GTP which converts the protein back to its inactivated state
What is the biggest barrier to cellular communication?
The cell membrane
Describe contact dependent cell signalling
- Both cells are in close contact
- the signalling molecule (transmembrane protein) remains attached to the signalling cells membrane
- target cell has receptor on its cell membrane
- cells close together to allow information to be exchanged
E.g. stem cells
Describe paracrine cell signalling
- short distance communication
- signalling molecule is soluble
- signalling molecule secreted in extracellular environment
- cells in close proximity and have the appropriate receptors will be able to detect the signalling molecule
- the closer the cell= more signal it can receive
Describe synaptic signalling
- Information transmitted from cell body of the axon
- Travels along the axon
- Transmitter (signalling) molecule released into the synaptic cleft
- Target cell binds the signalling molecule and respond to it
How long is the longest axon in our body?
1 meter Static nerve (from base of spine—>big toe)
Describe endocrine signalling:
- long distance
- signalling molecule in this case= hormones
- hormones travel in the bloodstream until they reach the target cell
- hormone binds to receptor on cell surface of target cell
E.g cancer cells
Describe autocrine signalling
- self signalling
- the cell secretes asignalling molecule
- receptors on its own surface detect this molecule and respond to it
E.g. cancer cells secrete growth hormones and they have growth hormone receptors thus activating themselves and keep proliferating
What is the ligand of the insulin receptor?
Insulin
What is the function of receptors?
To communicate signals to cells
Describe cell surface receptors?
- Integral proteins
- They will have “pocket”where the hydrophilic signalling molecule can bind
Describe intracellular receptors
(A carrier protein transports the small hydrophobic signalling molecule to the cell)
- signalling molecule detected by the receptor which can be in the nucleus of the cell
- this means that gene transcription can be effected
Describe the general components of signalling cascades
Ligand>receptor>intracellular mediations> effector enzymes> target proteins
What are second messengers?
Alter metabolism or affect effector enzymes that modulate target proteins
What are target proteins?
They alter gene transcription and cell behaviour
What are the main components of signalling pathways?
Ligand Receptor Intracellular mediator Effector enzymes Second messengers Target proteins
What is an agonist?
A ligand that induces a positive physiological response
What is an antagonist?
A ligand that represses a physiological response
Kinases phosphorylate proteins: what are the 3 main amino acids that can be phosphorylated?
Why?
Serine
Threonine
Tyrosine
- They all have OH groups
What is the requirement for phosphorylation?
Hydroxyl group
Describe phosphorylation as a molecular switch
- When the protein is “off” the protein kinase can hydrolyse ATP to ADP and add the P to the protein thus activating it “turns on” so the protein can pass on the signal
- protein phosphatases hydrolyse the phosphate off the protein and converts it back to its inactive form
What happens after a ligand dimer binds to the two receptor tyrosine kinases?
- the intracellular kinase domains are inactive in the monomeric form
- receptor dimerisation driven by ligand brings two kinase domains close together
- this activates the kinase domain of the receptor
- the kinase domains phosphorylate one another (autophorphoylation)
- cytosolic proteins can bind to the phosphorylated site and convey the signal further (thus amplifying the signal)
What helps GTPase enzymes to hydrolyse/displace GDP?
- GEF= guanine nucleotide exchange factor
- They remove GDP from GDPase and because in the cytosol there is a higher ration of GTP:GDP (10:1)
- GTP will then bind to GTPase
What helps GTPase hydrolyse GTP?
GAP: guanine activating protein
This returns GTPase to its inactive form
What are the consequences of phosphorylation and GTP binding?
- both act as molecular switches
- both can enhance signal strength (activation of many downstream effectors during their lifetime= amplification)
- both need to be turned off:
Phosphorylation needs to reverses by phosphatases
GTPases have intrinsic ability to hydrolyse GTP to GDP but GTPase activating proteins can enhance activity
Describe the inactivation of receptor signalling
- low pH in the endosome
- encourages ligand to dissociate from the receptor
- receptor rechecked back to plasma membrane
Or - ligand receptor complex degreaded in a lysosome
Or - ligand receptor inactivation directly by enzymes
Or - inactivation of signalling protein
Or - production of inhibitor protein
What are the function of feedback loops within a signalling pathway?
Allows signalling can be increased or inhibited (fine tuned)
MAP kinases use both types of switch
Phosphorylation
Small monomeric G proteins
Cell signalling ling: describe contact dependent cell signalling?
- Signalling molecule stays attached to the signalling cells membrane
- cells are close together to be able to exchange information
E.g. stem cells
Cell signalling: describe paracrine communication
- short distance communication
- signalling molecule soluble
- signalling molecule secreted into extracellular environment
- cells that have appropriate receptors will be able to detect the molecule
- the close the cell is to the transmitter cell, the more signal it can receive
Cell signalling: describe synaptic signalling
- long/ short distance communication
- information transmitted from the cell body
- along the axon to the axon terminal
- neurotransmitters released into the synaptic cleft
- the target cell then binds to the signalling molecule and respond to it
Cell signalling: describe endocrine signalling
- long distance signalling
- production of hormones
- that travel in the bloodstream
- until they reach the target cell
- which has appropriate receptors on its cell surface
How do RTK use monomeric GTPase as molecular switches?
- When GTPases are bound to GDP it is in its “off” form
- when a signal is received, GDP is exchanged and replaced by GTP- “on” (active form)
- the GTPase then hydrolyses GTP thus returning it to its inactive conformation
What are intracellular mediators?
Proteins that transmit the signal from the receptor to the effector enzyme
