chapter 8: cell signalling Flashcards
what are the three stages of cell signalling?
- ligand-receptor interaction
- signal transduction
- cellular responses
stages of cell signalling
what happens during ligand-receptor interaction?
- target cells possess receptor proteins which are able to bind specific ligands
- the ligand has a specific 3D configuration that is complementary to the binding site of the receptor
- binding of the ligand to its receptor generally causes the receptor protein to undergo a conformation change
- which activates the receptor
- as a result, the chemical information is transmitted from the extracellular environment into the cell
what are plasma membrane receptors and what binds to them?
- these receptors are embedded on the cell surface membrane
- they are transmembrane proteins
signal molecules that bind to plasma membrane receptors include: - water soluble/ hydrophilic molecules which cannot interact with the phospholipid bilayer of the plasma membrane to pass through it freely
- molecules which are too large to pass through the plasma membrane
conformational change which result in direct activation of receptor
what are ion channel receptors/ ligand-gated ion channel?
- ligand-gated ion channel is a type of membrane receptor containing a region that acts as a ‘gate’
- that opens or closes when the receptor changes shape
- it regulates the passage of specific ions like Na+ and Ca2+
ion channel receptor
what is the structure of the ion channel receptor?
- ligand-gated ion channel forms a protein pore in the membrane
- it contaisn an extracellular signal-binding site and a region that acts as a ‘gate’
- the ‘gate’ opens and closes in response to the binding of ligand to the receptor protein to allow specific ions to flow through the channel
- hydrophilic channel is also specific to specific ions
ion channel receptor
how does the ion channel receptor interact with its ligand and pass on the signal?
- the gate of ligand-gated ion channel remains closed until a specific ligand binds to the receptor
- binding of ligand to receptor results in a conformational change in the ligand-gated ion channel
- causing the gate to open
- specific ions flow through the ion channel
- resulting in a change in the intracellular concentration of the particular ion
- triggering cellular responses
- once the specific cellular response has been carried out
- the ligand disscoiates from the receptor
- causing the ion channel to close
- this terminates the signal
GPCR
what is a G-protein coupled receptor?
- it is a cell-surface transmembrane receptor that works with the help of G-protein
- G-protein: a protein that binds to guanine nucleotides GTP or GDP
what is the structure of the GPCR receptor?
- a GPCR consists of seven transmembrane a-helices
each GPCR receptor contains:
- an extracellular ligand-binding site
- a intracellular/cytoplasmic G-protein binding site
the G protein functions as an on-off switch, depending on which of the two guanine nucleotides is bound
how does the GPCR interact with its ligand and pass on the signal?
when the G-protein system is inactive, G-protein is bound to GDP
- upon binding of the signal molecule on the extracellular ligand-binding site of GPCR, the receptor is stimulated to undergo a conformational change
> GPCR becomes activated - the cytoplasmic side of the activated GPCR binds to the inactive G-protien, causing a conformational change in the G-protein
- GDP is displaced from G-protein by GTP
> the G-protein becomes activated - activated G-protein binds and activates other effector proteins like adenylyl cyclase
- once specific cellular responses have been carried out, GTP is hydrolysed to GDP by the intrinstic GTPase ezyme in the G-protein
- G-protein leaves effector protein and returns to its inactivated form, ready and availible for reuse again
- hence, the GTPase function of the G protien allows the pathway to be shut down rapidly
- when the extracellular signal molecule is no longer present
which structural feature of GPCR gives it this function?
fucntion: it allows GPCR to be stably embedded in the cell surface membrane
- secondary structure with seven transmembrane a-helices
- the exterior surfaces of the helices have many amino acid residues with non-polar, hydrophobic R groups
- these amino acid residues face the non-polar fatt acid tails of the phospholipids in the cell surface membrane
- interacting with the fatty acid tails via hydrophobic interactions
which structural feature of GPCR gives it this function?
function:
- has a complementary shape to the ligand to allow binding of a specific ligand on the extracellular ligand-binding site of the GPCR
- has a complementary shape to the G protein and allows the binding of the G protein in the cytoplasm to the cytoplasmic G protein binding site of the activated GPCR
- transmembrane protein that has specific loops between the a-helices
these loops form these binding sites:
- an extracellular ligand-bindign site
- a intracellular G protein binding site
which structural feature of GPCR gives it this function?
function: to allow binding sites of different GPCRs to have different shapes
> so that a large variety of ligands and G proteins can bind to different GPCRs
> allows different ligands to activate different/ same cell signalling pathways
- eventhough all GPCRs have seven trasnmembrane a-helices
- the specific amino acid sequences at both the ligand and G-protein binding site differ for different types of GPCR
what is the structure of receptor tyrosine kinase?
tyrosine kinase receptor contains:
- an extracellular signal-binding site
- a single a-helix trasnmembrane region
- an intracellular tail containing several tyrosine amino acid residues
> the intracellular tail also functions as tyrosine kinase enzyme
- in the inactive state, tyrosine-kinase receptors exist as monomers
how does tyrosine kinase receptor interact with its ligand and pass on the signal?
- when ligand binds to each other of the two tyrosine-kinase receptor monomers
- the receptor monomers aggregate, forming a dimer
- dimerisation activates the tyrosine kinasse region on each receptor monomer - each activated tyrosine kinase region phosphorylates the other receptor monomer at the tyrosine residues on the intracellular tail
- (additions of a phosphate group from an ATP molecule)
- this fully activates the receptor, forming a phosphorylated dimer - the fully activated tyrosine-kinase dimer binds and activates many specific intracellular relay proteins via phosphorylation
- each activated tyrosine kinase dimer can activate many different intracellular proteins simultaneously and trigger many different transduction pathways and cellular responses
- after specific cellular responses have been carried out, the signal is termindated via the removal of the ligand
what is a difference between RTK and GPCR?
- one activated receptor tyrosine kinase dimer may activate ten or more different transduction pathways and cellular responses simultaneously
- RTK: its ability of a single ligand-binding event to trigger so many pathways simultaneously is a key difference from GPCR
what is signal transduction and what are the two main mechanisms?
- ligand-receptor binding intiates a signal transduction pathway inside the cell
- a signal transduction pathway involves a sequence of changes in a series of relay molecules within the cell, which result in a specific cellular response
two main mechanisms:
- protein phosphorylation
- activation of a second messenger
what is protein phosphorylation?
- information is passed from the ligand to intracellular proteins through a series of phosphorylation of intracellular relay proteins
- upon ligand binding, a relay protein is activated and initiates a phosphorylation cascade
- many relay proteins are protein kinases and they act on other protein kinases
- a phosphorylation cascade consists of a series of protein kinases which shuttle between the phosphorylated (active) and dephosphorylated (inactive)
- each activated protein kinasee phosphorylates its succeeding protein kinase by transferring a phosphate group from ATP to their substrate proteins, activating them
- the activation of the last protein in the pathway results in a cellular response to the signal
- in the absense of extracellular signal, the signal-transduction pathway is turned off by protein phosphatases
- which are enzymes that remove the phosphate groups from proteins
- by dephosphorylating and inactivating protein kinases,
- phosphatases provide a mechanism for shutting down the signalling pathway and cellular response
what are second messengers and what are the two most common second messengers?
- many signalling pathways also involve small, non-protein water soluble molecules called second messengers
- the ligand is the first messenger
- as second messengers are small and water soluble, they can readily spread throughout the cell by diffusion
- they are responsible for relaying the signal from the cell surface to target moelcules inside the cell in order to elicit specific cellular responses
- second messengers participate in pathways initiated by both G protein linked receptors and tyrosine kinase receptors
the two most common sencond messengers are
- cyclic adenosine monophosphate (cAMP)
- calcium ions (Ca2+)
second messenger
what is cyclic adenosine monophosphate? (cAMP)
- cAMP is made from ATP catalysed by adenyly cyclase, an enzyme embedded in the plasma membrane
- cAMP is a component of many G-protein signaling pathways as G protein activates adenylyl cyclate
- the immediate effect of cAMP is usally activation of serine/threonine kinase called protein kinase A
- the effect of cAMP is short lived
- it is inactivated by phosphodiesterase, an enzyme that converts it to AMP
second messengers
how does the calcium ions function?
- calcium ions can function as second messenger because its concentration in the cytoplasm is much lower than outside the cell
- cells use Ca2+ as second messengers in both G protein and RTK pathways
- many signalling moelcules in animals induce responses in their target cells via signal transduction pathways that increase the cytosolic concentration of Ca2+
- increasing the cytosolic concentration of Ca2+ causes many responses in animal cells
- like muscle cell contraction, secretion of certain substances and cell division
what is signal termination and how can it be carried out?
- after the specific cellular response have been carried out , the signal is terminated
- signal termination has to be carried out in order for the cell to be continually receptive and sensitive to regulation by signalling
signal termintion can occur by:
- dissociation of ligand from receptor followed by destruction/ inactivation of ligand
- deactivation of a signal transduction protein ( like dephosphorylation of protein kinases by protien phosphatase)
- degradation of second messenger
what are the cell signalling pathways that allow for coordination of signalling pathways and also contribute to the specificity of the response?
- different cells can respond differently to the same ligand-receptor interaction
- depending on the type of proteins that relay and respond to the signal
- a single tpe of ligand can trigger different cellular responses in different types of cells at any one time - the same ligand binding to different receptors can also trigger different responses
- a pathway that is triggered b a single kind og ligand can diverge to give two different responses
- a single type of ligand can trigger numerous responses in a cell all at once through activation of multiple transduction pathways - two pathways triggered by seperate signals can converge to modulate a single response
INSULIN AND RTK SIGNALLING
describe the ligand- receptor interaction.
- ligand: insulin
- receptor: RTK receptors on target cells
- insulin bind to RTK receptors at cell surface membrane
- dimerisation activates the tyrosine kinase region on each monomer
- each activated tyrosine kinase region phosphorylates the other receptor monomer at the tyrosine residues on their intracellular tail, fully activating the receptor
INSULIN AND RTK SIGNALLING
describe the signal transduction
- fully activated RTK receptors activate a series of protein kinases in a phosphorylation cascade
INSULIN AND RTK SIGNALLING
describe the cellular response
- activated intracellular proteins cause vesicles with glucose carrier proteins to move to the cell surface membrane and fuse with it
- glucose carrier proteitns are inserted into the membrane
- more glucose carrier proteins along membrane
- allows for an icnrease in uptake of glucose by cells
other cellular responses:
- increase in activity or synthesis of enzymes involved in glycogenesis, respiration and fat synthesis
- glycogenesis: synthesis of glycogen
- decrease in activity or synthesis of enzymes involved in glycogenolysis and gluconeogenesis
glycogenolysis: breakdown of glycogen
gluconeogenesis: formation of glucose from non-carbohdrate sources
signal termination: after the specific response has been carried out,
- insulin is released from receptors
- dephosphorylation of protein kinases by phosphatase enzymes
- endocytosis of glucose carrier proteins, carrier proteins are removed from the cell surface membrane
glucagon and G protein signalling
describe the ligand receptor interaction.
- ligand: glucagon
- receptor: GPCR on liver cells
- second messengers: cAMP
- glucagon binds to G protein couple receptors at the cell surface membrane
- the receptors undergo a conformational change and the receptors become activated
- the activated GPCR binds to G protein
- the G protein undergoes a conformational change causing the GDP to be displaced by GTP
- the G protein becomes activated
glucagon and G protein signalling
describe signal transduction
- activated G protein activates adenlyl cyclase which catalyses the conversion of ATP to cAMP
- cAMP then activates protein kinase A
- the activated protein kinase A then phosphorylates other protein kinases in a serries of phosphorylation cascade until it reaches the final protein
- the final protein to be activated is enzyme glycogen phosphorylase
glucagon and G protein signalling
describe the cellular respons
- glycogen phosphorylase casues the breakdown of glycogen to glucose
other cellular response
- increase in activity or synthesis of enzymes involved in gluconeogenesis
singal termination, after the specific response has beeen carried out,
- glucagon is released from receptor
- GTP on G protein is hydrolysed to GDP by intrinstic GTPase enzyme in G protein
- cAMP is degraded to AMP by phosphodiesterase
explain why insulin receptors are found on the cell surface membranes of target cells and never within the cells?
- insulin is a large/ hydrophilic
- and will be repelled by the hydrophobic core made by fatty acid tails of the phospholipid bilayer
- thus, insulin cannot pass through the cell surface membrane but interact with the receptor by binding to its extracellular ligand binding site
what are the advantages of a G-protein signalling pathway?
- Allows for signal amplification, where a single glucagon ligand results in the production of many second messenger molecules, such as cAMP, leading to a large cellular response.
- Ensures specificity of response, where only glucagon molecules with a complementary shape to the ligand binding site on the GPCR receptor can bind, activating the signaling pathway in specific cells.
- Provides the ability for control at multiple points to fine-tune the cellular response, as the levels of GTP, G-protein, or adenyl cyclase can be regulated to adjust the overall cellular response.
explain the significance of cell signalling pathways.
- Cell signaling pathways allow for cellular responses to maintain a constant internal environment.
- They enable signal amplification, as each catalytic step activates more products than the preceding one, leading to a larger response.
- A small number of extracellular signals can trigger a large cellular response.
- Different pathways can converge to modulate a single response.
- A single signal can diverge to produce multiple cellular responses.
- Specificity of response is ensured by the presence of specific receptors and relay proteins in target cells.
Step-by-Step Explanation:
1. G-protein Activation:
- When a signal molecule binds to the GPCR, the G-protein is activated (GDP is replaced by GTP).
- The activated G-protein binds to adenylyl cyclase, activating it.
- Formation of cAMP:
- Adenylyl cyclase (an enzyme embedded in the plasma membrane) catalyzes the conversion of ATP into cyclic AMP (cAMP).
- cAMP is a secondary messenger that relays the signal inside the cell. - Activation of Protein Kinase A (PKA):
- cAMP binds to and activates a protein called protein kinase A (PKA)
- PKA is a serine/threonine kinase, meaning it phosphorylates proteins at serine or threonine residues, which leads to downstream effects (e.g., activating or deactivating target proteins).
- Short-Lived Effect of cAMP:
- The action of cAMP is short-lived because it is quickly inactivated by phosphodiesterase.
- Phosphodiesterase breaks down cAMP into AMP, stopping the signal.
