L16 - Signal Transduction Flashcards
What is signal transduction? (Basic)
A way in which cells gain info about the environment involving a process of converting signals into cellular responses in which the signalling molecule acts as a ligand.
What is signal transduction? (Complex)
A ligand binds to a specific structural site on the extracellular or membrane-spanning domains of the receptor. Ligand binding to receptor causes conformational change of the receptor activating messengers. This induces specific cellular responses.
Why is signal transduction relevant?
Mediates direct cell to cell comms, coordinates metabolic processes within cells, growth and differentiation of tissues, synthesis and secretion of proteins, and aggregation of free living cells for sexual mating or differentiation under certain conditions enviro conditions in eukaryotic microorganisms
How does communication by extracellular signals work?
Receptors are activated by molecules binding, changes in conc of metabolites, or physical stimuli. Generally, ligand binding to a receptor leads to activation of transcription factors in the cytosol, permitting them to translocate into the nucleus and stimulate transcription of their target genes.
Signalling molecules can act over an array of distances. Signalling by soluble extracellular molecules can be classified into three types based on distance. What are these types?
Endocrine, paracrine, autocrine.
What is endocrine signalling? With e.g.
Signalling molecules released by a cell affect target cells distant from the site of synthesis. E.g. hormones in animals, carried in blood from its site of release to its target
What is paracrine signalling?
Signalling molecule released by a cell affects target cells only in close proximity. E.g. many growth factors, conduction by a neurotransmitter of a signal from one nerve cell to another or from nerve cell to muscle cell.
Can some signalling molecules act on short and long range? E.g?
Yes, epinephrine, neurotransmitter (paracrine) and systemic hormone (endocrine)
What is autocrine signalling? E.g.
Cells respond to substances they themselves released. E.g. cultured cells which secrete their own growth factors, tumour cells overproduce and release growth factors which stimulate proliferation of themselves and adjacent nontumour cells.
What is the intracellular signal transduction?
Pathways inside the cell that transduce signals downstream from cell-surface activation. Ligands bind to cell surface receptors leading to temporary change in concentration of low-molecular-weight intracellular signalling molecules. The altered intracellular conc of one or more second messengers leads to activation of intracellular protein within the signal transduction pathway.
What are some common second messengers?
Cyclic nucleotides (cAMP, cGMP), lipid messengers (DAG, IP3), ions (Ca2+)
What is the adenyl cyclase pathway?
External protein binds to the G-protein coupled receptor, which activates adenyl cyclase, which then releases cAMP, which activates protein kinase A, which activates enzyme within the pathway, which produces the desired product.
Why is Ca2+ useful as a second messenger?
Can be viewed in signal transduction
What help transduce signals downstream from activated cell-surface?
Proteins
What proteins help transduce signals downstream from activated cell-surface
G-proteins - guanine nucleotide-binding proteins, otherwise known as molecular switches, part of the enzymes called GTPases. Protein kinases - enzymes that catalyse the addition of phosphates to a substrate protein. Phosphatases - enzymes that catalyse the removal of a phosphate from a substrate protein
What do G-proteins do?
Interact with other proteins downstream of the signal transduction pathway to change and perpetuate the signal. Switches between on or off state.
What are the G-protein on or off states called?
GTP-bound on, GDP-bound off.
What happens in the G-protein on state?
In the active GTP-bound on state, two protein domains are bound to the terminal phosphate of GTP allowing the protein to bind to and activate other downstream signalling proteins. Release of the phosphate by GTPase-catalysed hydrolysis causes domain 1 and 2 to relax into the GDP-bound off state.
What does activation of cell-surface receptors result in.
It results to directly or indirectly changes in protein phosphorylation through activation of protein kinases or protein phosphatases
What are the types of protein kinases?
Ones that add the phosphate group to the hydroxyl group on tyrosine residues, ones that add the phosphate group to the hydroxyl group of serine and threonine residues.
What are G protein-coupled receptors?
Contain 7 membrane-spanning regions, N-terminal segment on the exoplasmic face (outside of the cell), C-terminal segment on the cytosolic face (inside the cell) of the plasma membrane
What does the G protein-coupled receptor family include?
Receptors for numerous hormones and neurotransmitters, light-activated receptors in the eye, thousands of odorant receptors in the mammalian nose
What is ligand-induced activation of effector proteins associated with G protein-coupled receptors?
The trimeric G-proteins are tethered to the membrane by covalently attached lipid molecules. Ligand binds receptor, receptor binds G-protein, exchange of GDP with GTP, alpha part of the G protein binds to and activates an effector protein, hydrolysis of GTP terminates signalling leading to reassembly of the trimeric form, returning to resting state.
Can effectors be both activated or inhibited by G protein-coupled receptors?
Yes, e.g. hormone induced activation and inhibition of effector in adipose. Ligand binding to G stimulatory-coupled receptors causes activation of adenylyl cyclase, whereas ligand binding to G inhibitory-coupled receptors causes inhibition of adenylyl cyclase.
How do G-proteins activate ion channels?
Binding of acetylcholine triggers activation of the G protein. The released G-beta subunit binds to and opens the associated effector, a K+ channel.
Ex of light activated G protein coupled receptors
The human retina contains two types of photoreceptors, rods, and cones, that are the primary recipients of visual stimulation. Cones are involved in colour vision (GPCR = iodopsin), rods are stimulated by weak light (GPCR = rhodopsin). Rhodopsin, is localised to the membrane disks of rod cells. The trimeric G protein coupled to rhodopsin, often called transduction is only found in rod cells.
Ex Rhodopsin - induced closing of cation channels in rod cells
In dark-adapted vision levels of cGMP keep the nucleotide-gated non-selective cation channels open. Retinal molecule inside an opsin protein absorbs light activating it, activated opsin binds the G protein mediating GDP to GTP replacement. The free alpha subunit of the G protein activates cGMP phosphodiesterase (PDE) by binding its inhibitory gamma subunit, the PDE inhibitory gamma subunit dissociate from the catalytic alpha and beta. No longer inhibited, the alpha and beta subunits convert cGMP to GMP. Decrease in cGMP in the cytosol leads to the dissociation of gCMP from the nucleotide-gated ion channel closing the channel, hyperpolarising the membrane.
How do G protein d activate gene transcription?
The intracellular signal-transduction pathways have short term effects on the cell - modulation of the activity of pre-existing enzymes or other proteins, leading to changes in cell metabolism or function (most GPCR pathways), or long term effects on the cell due to activation or repression of genetranscription.
How does activation of gene expression following ligand binding to G protein-coupled receptors work?
Receptor binding GPCR leads to activation of adenyl cyclase, releases cAMP which leads to activation of PKA, catalytic subunits of PKA move to the nucleus, the subunits phosphorylate and activate the transcription factor CREB, CREB associated with a co-activator which stimulates various genes controlled by CRE.
