Cell Signalling III Flashcards
What are the types of cell-surface receptor proteins?
Ion-channel coupled receptors
G-protein coupled receptors
Enzyme-coupled receptors
What are the typical ion channel coupled receptors?
Transmitter gated ion channels induced by neurotransmitters
What is the effect of ion channel coupled receptor binding?
Can either increase or decrease of ion permeability across the membrane
Name a common example of a hormone/neurotransmitter that acts on ionotropic receptor in postsynaptic cells:
Acetylcholine
How do G protein coupled receptors work?
They indirectly regulate another membrane bound target protein and involve trimeric GTP-binding proteins which interact with the receptor and the effector
What are enzyme-coupled receptors?
Receptors with intracellular enzymatic domains that start enzymatic action after binding of ligand to receptor.
What are second messengers?
Intracellular molecules that relay signal through the cell after initial binding of first messenger.
What kind of molecules can secondary messengers be?
Can be small molecules (GTP, cGMP, cAMP, etc)
Can be water soluble and in the cytoplasm or lipid soluble and capable of diffusing around the plane of the membrane.
Can be proteins (eg SHC, Grb2)
Pass signal through the cell and ultimately binding to and changing effector protein
What do effector proteins do?
They are responsible for modifying cell behaviour and can give final response of cell to original signal.
What is the purpose of intracellular messengers?
Transforming the signal into a molecular form that can be passed along the pathway to stimulate a response. (creates a practical messenger response)
Allows signal to be relayed from primary site to response production site (transmits signal from one part of the cell to another as needed)
a single extracellular molecule can have a much more pronounced effect on the cell (Amplifies signal to strengthen response)
Signal can be allowed to produce a diverse range of responses to the same signal. (diversifies signal)
Relay signal may be modulated by other factors along the pathway (regulation of signal)
What are 2 common modes of intracellular signalling?
GTP binding to replace GDP in response to a signal
Phosphorylation of protein via a protein kinase that is activated by ligand binding
How do some bacteria manipulate G protein coupled receptors?
Some bacterial toxins cause disease by altering the activity of G proteins.
Describe the structure of a GPCR:
Polypeptide chain traverses membrane as 7-alpha helices
Cytoplasmic portion binds to G protein inside the cell
Receptor structure depends on what molecule will bind to it. small molecules bind deep in the membrane and large proteins require large extracellular domains.
What subunits are G proteins composed of?
Alpha
Beta
Gamma
How do the G protein subunits attach to the membrane?
Both βγ & α subunit have lipid tails that help attach to membrane
What happens when G proteins are activated?
Unstimulated G protein has GDP bound to it. When activated alpha subunit loses affinity for GDP and gains affinity for GTP.
How does GPCR activation trigger secondary messenger system?
Activated GPCR activates G proteins – α subunit exchanges
GDP for GTP
Unstimulated state, both receptor and G protein inactive binding extracellular signal molecule to receptor changes
conformation.
Altered conformation of G protein α subunit exchange GDP to GTP
additional conformation change is created resulting in
α and βγ complex dissociating to interact with target proteins
What are possible functions of G proteins?
G proteins can interact with ion channels (acetylcholine in heart cells)
G proteins can activate membrane bound enzymes that produce small messenger molecules (adenylyl cyclase or phospholipase)
What does adenylyl cyclase do?
Produces cAMP
what does phospholipase C do?
Produces inositol triphosphate and diacylglycerol
What does inositol triphosphate do?
Promotes accumulation of calcium which is another signalling molecule
How does cAMP activate its effects?
It binds to regulatory subunits to release catalytic subunits.
How does a rise in intracellular cAMP concentration alter gene transcription?
cAMP activates cyclic-AMP-Dependent Protein Kinase (PKA) which moves to nucleus and phosphorylates transcription factor thus resulting in target gene transcription.
How does a rise in intracellular cAMP concentration activate enzymes?
Rise in cAMP activates PKA
PKA phosphorylates and activates enzyme which causes activation of enzyme
What is PKA?
Cyclic-AMP-Dependent Protein Kinase (PKA)
How does G protein stop acting after being activated? (negative feedback)
G-protein alpha subunit switches itself off by hydrolyzing bound GTP to GDP. Loss of GTP inactivates alpha subunit and so it reassociates with βγ complex
How does cholera toxin modify the G protein activation system?
Protein enters cells that line the intestine and modifies alpha subunit of G protein preventing GTP hydrolysis and so G protein is constantly active resulting in excessive outflow of Cl- and water into the gut
What other method can GPCRs exert their effects?
Some GPCRs exert effect through G proteins that activate membrane bound enzyme
phospholipase C-β.
Two second messengers are produced from hydrolysis of PI(4,5)P2
