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What are the four types of Signalling?
Which signalling system uses local mediators?
Paracrine. Endocrine uses hormones and Synaptic uses neurotransmitters .
Which behavioural change is faster, Allosteric or Protein Production?
Allosteric is much faster than protein production.
**** Acetylcholine 1 contraction in skeletal muscles but 2 in cardiac muscles.
A) Increases, Decreases.
B) Decreases, Increases.
**** B) Decreases, Increases.****
What is a Morphogen?
A signal molecule creating a gradient which cells respond to. They are used in development.
What are the three classes of Receptor Proteins?
- G-Protein Coupled.
- Ion-Channel Coupled.
- Enzyme Coupled.
What are second messengers?
Intracellular molecules secreted as a result of extracellular stimulus.
WHat are the eight intracellular signalling proteins?
What are the two types of G-protein?
Monomeric and Trimeric.
When is a G Protein Switched "On".
When it has GTP.
What other molecular switch system exists that is not a G-protein.
Phosphorylation with Kinases and Phosphatases.
What is a phosphorylation cascade?
One Kinase is Phosphorylated, which phosphorylates another and another etc.
What is the main Protein Kinase?
Why are Serine and Threonine often phoshporylated?
They have OH groups to phosphorylate.
What is another, less common, class of Kinase (Apart from Serine/Threonine).
What is one similarity between Monomeric and Trimeric G-Proteins?
They are both Deactivated by GAF's.
How is a Trimeric G-Protein Phosphorylated?
A G-Protein Coupled Receptor will act like a GEF.
How is a Monomeric G-Protein Activiated?
Guanine Exchange Factors Switch GDP for GTP.
How do Scaffold Proteins increase speed and efficiency?
By bringing and holding proteins together.
What are the three types of Scaffold Assembly?
- Assembled on Receptor
- Assembled on Membrane (Phosphorylated Membrane Lipids).
What is the most commonly Phosphorylated Membrane Lipid?
What is the role of Interaction Domains?
To Interact with a specific Molecule.
Where does the Sarc Homology 2 (SH2) domain bind?
Which Molecules bind to Phosphorylated Tyrosine?
- Sarc Homology 2
- Phosphotyrosine Binding Domains.
What does Sarc Homology 3 bind to?
Short Proline Rich Sequences.
What do Pleckstrin Homology Domains Bind to?
Charged Head Groups of Specific Phosphoinositides.
How might a cell produce an "All or Nothing" response?
Which Feedback loop is involved in differentiation?
Exaggerated positive feedback.
What is the main role of Short Delay Negative Feedback?
How does Receptor Sequestration work?
The Receptor-Ligand is taken into a Vesicle, the Ligand is Dissociated and the Receptor Replaced.
How does Receptor Down Regulation work?
The receptor-ligand complex is endocytosed into a vesicle which becomes a lysosome destroying everything.
How does Receptor Incactivation work?
The receptor is inactivated.
How does Inactivation of Signalling Protein work?
The intracellular signalling protein (Second Messenger) is inactivated.
How does Production of Inhibitory Proteins work?
Inhibitory Proteins block a Receptor's signalling pathway.
Where might you find a G-protein coupled receptor?
In the plasma membrane.
What is the basic structure of a G-Protein Coupled Recepor?
A seven pass transmembrane protein.
What Protein found in the eye is an example of a G-Protein Coupled Receptor?
What is the basic structure of a Trimeric G?
- Three Subunits; Alpha, Beta and Gamma.
- "Live" on cytosolic side of Membrane.
GCPR's and G-Proteins are the same thing. True or False?
False. GCPR's activate G-Proteins.
How does Activation of the Trimeric G-Protein work?
And Extracellular Signal Binds to the Cell Surface Receptor, Activating the G-Protein Coupled Receptor. The GCPR then acts like a Guanine Exchange factor, causing the G-protein to release it's GDP so it can bind GTP. The association of GTP changes the G-Proteins configuration.
What are the conformational changes in Activated Trimeric G-Proteins?
- 1. A conformational change results in the Alpha Sububit dissociating from the Beta-Gamma Subunits. This exposes previously covered sites whithin the protein.
- 2. Interactions between Alpha and Beta-Gamma subunits and these sites modulate an Enzymes or Ion Channels.
- 3. Somtimes Alpha and Beta-Gamma Dissociate completely.
Which Trimeric G-Protein Subunit "holds" the bound GDP?
The Alpha Subunit.
Hydrolysis of bound GTP in G-Protein Signalling is ofren short, why? (G-Proteins usually take forever).
Either a Target Protein or Regulator of G-Protein Signalling acts like a G-Protein Activating Factor.
What is Cyclic AMP (cAMP) in relation to Cell Signalling?
A small intracellular mediator.
How is Cyclic AMP produced?
Adenylyl cyclase produces cAMP.
Where is Adenylyl Cyclase found?
On the Plasma Membrane.
What does Cyclic AMP Phosphodiesterase do?
Breaks down cAMP into Adenosine 5' Monophosphate.
Why is it important for cAMP to be rapidly produced and degraded?
To allow for quick response time.
Why might it be useful to increase cAMP production but not cAMP degradation?
To allow for signalling.
How are cAMP concentrations increased?
G-Coupled Exchange Factors Activate a Stimulatory G-Protein that activates Adenylyl Cyclase.
How is cAMP decreased?
G-Protein Coupled Recptors activate inhibitory G-Proteins that inhibit Adenylyl Cyclase by regulating Ion Channels.
With Respect to Cell Signalling (cAMP) how does the cholera Toxin work?
- 1. The Cholera Toxin Ribosylates ADP on the Stimulatory G-Protein's Alpha Subunit. As a result Hydrolyses cannot occur and the Gs Protein is permenantly switched on.
- 2. This Permenant Activation causes Adenylyl Cyclase to continuously produce cAMP which affects Ion channels, causing Diarrhoea.
Starting with an Extracellular Signal, detail the events leading to phosphorylation of Serine, Threonine or Tyrosine on a Target Molecule.
Extracellular Signal -> G-Protein Coupled Receptor -> Activated Trimeric G-Protein -> Activated Adenylyl Cyclase -> cAMP -> cAMP Dependant Kinase -> Target Molecule.
What is the Structure of cAMP Dependant Protein Kinase?
- Two Regulatory Subunits
- Two Catalytic (Kinase) Subunits.
How does cAMP Dependant Kinase Function?
- cAMP binds to the regulatory subunits making them dissociate.
- The dissociation activates the Kinases.
What is the purpose of binding cAMP to specific locations.
To allow for specific localized responses to cAMP.
How is cAMP Dependant Kinase Localized?
A-Kinase anchoring proteins binds to the cAMP-dependant Kinase Regulatory rubunits and to the specific molecule or Signalling Protein.
Give one example of each of cAMP-Dependant Kinase and cAMP acting (Independantly).
- 1. cAMP activates cAMP Dependant Kinase which phosphorylates a CRE protein allowing for transcription.
- 2. Activation of the Monomeric G-Protein, rap-1 by cAMP which leads to increased Cell Adhesion.
Starting with an Extracellular Signal and Ending with Diacylglycerol+Inositol 1,4,5-Triphosphate, describe the steps in the inositol phospholipid pathway.
Extracellular Signal -> G-Protein Coupled Receptor -> Gq -> Phospholipase c-beta -> Cleavage of PIP2 -> Diacylglycerol + Inositol 1,4,5 Triphosphate.
In the inositol Phospholipid Signalling Pathway what is the Inositol 1,4,5 Pathway (After Cleavage)?
Inositol 1,4,5 Triphosphate (IP3) -> Diffuse through cytosol (Water Soluble) -> ER Membrane -> IP3-Gated Ca2+-release channels -> Calcium Out.
In what three ways is the Calcium Response terminated in the Phospholipid Signalling Pathway?
- IP3 is rapidly dephosphorylated to IP2.
- IP3 is phosphorylated to IP4 (Further Signalling).
- Ca2+ is pumped out of the cell.
In the Inositol Phospholipid Signalling Pathway, what are the Diacylglycerol Pathways?
- 1. Further Cleavage in to Arachidonic Acid can be a signal or is Converted into an Eicosanoid.
- 2. Remains membrane bound and activates Protein Kinase C.
How is Protein Kinase C activated?
- 1. The Ca2+ influx vrought on by IP3 causes Inactive Protein Kinase C to move to the membrane.
- 2. On the membrane Protein Kinase C is activated further by Ca2+ as well as Diacylglycerol and Phosphorylated Serine.
Why are Scaffold Proteins useful?
They can mediate which molecules are activated by a specific protein/enzyme.
Why is Ca2+ important in signal transduction?
It is an intracellular mediator used everywhere.
Which recptors are involved in Ca2+ influx?
- Ryanodine Receptors.
- IP2 Receptors.
What is the effect of Ca2+ on IP3 receptors?
- They are activated only when IP3 is present.
- High Ca2+ causes inactivation.
What is Calmodulin?
A Cellular Receptor that binds to Ca2+.`
What is the structure of Calmodulin?
A single polypeptide chain with four high affinity Ca2+ binding sites.
How is Calmodulin activated?
At least two Ca2+ ions bind to it's sites, causing a conformational change.
Does Calmodulin have any enzymatic activity?
No, it is just a receptor.
What is one role of Calmodulin?
(Hint: What is it coupled .with?)
- To control Ca2+levels in the cell.
- Ca2+ binds to Calmodulin which activates an ATP dependant pump that removes excess Ca2+.
What is a Ca2+/Calmodulin-Dependant Kinase?
A Serine/Threonine Kinase relying on the activity of Calmodulin for Activation.
What Ca2+/Calmodulin-Dependant Kinase (CaM-Kinase) is commonly found in the Nervous System?
What are the two key properties of CaM-Kinase II?
- Molecular Memory
- Frequency Decoder
What is Autophosporylation?
When a Kinase Phosphorylates itself.
What is an example of a Kinase capable of Autophosphorylation?
How does CaM-Kinase II's memory work?
Activation by Calmodulin/Calcium -> Autophosphorylation -> Remains Active
How is CaM-Kinase II deactivated?
An abundance of Serine/Threonine phosphatases overwhelm the autophosphorylation of CaM-Kinase II, switching it off.
Trimeric G-Proteins often alter Ca2+ or cAMP concentrations. What do they alter in Cytoskeleton regulation?
A GEF that activated the monomeric G-protein, Rho.
What is Rho?
A Monomeric G-Protein involved in actin regulation.
What is an example of a G-Protein activating an ion channel?
- Acetylcholine affecting heart rate.
- Acetylcholine -> GCPR -> Gi -> Adenylyl Cyclase Inhibited (α) + K+ Channels opened (βγ) -> Less Depolarization.
What are the key proteins in Olfaction and Vision?
- Nucleotide-Gated Ion Channels
Starting with an Olfactant, how is an action potential generated in Olfactory receptors?
- Oderant -> Olfactory Receptor -> GOlf -> Adenulyl Cyclase -> cAMP -> cAMP Gated Channels -> Na+ in -> Depolarization.
Give an example of a Cyclic-Nucleotide.
- Cyclic Adenosine Monophosphate (cAMP).
- Cyclic Guanosine Monophosphate (cGMP).
What Cyclic-Nucleotide does vision use?
Cyclic Guanosine Monophosphate (cGMP).
What two enzymes regulate cGMP?
- Guanylyl Cyclase
- cGMP phosphodiesterase
What are the fastest G-protein responses?
Rod cells are used in 1 vision, whereas Cone cells are used in 2 vision.
a) Night, Colour
b) Colour, Night
a) Night, Colour
How does visual Transduction work?
Photon -> Rhodopsin -> Gtransducin ->Cyclic GMP phosphodiesterase (α) -> cGMP hydrolysis -> cGMP-Dependant Channels close -> Hyperpolarization.
In Termination of Visual Transduction, describe the steps that reduce activation of Transducin (Gt).
Start with Rhodopsin Kinase.
Rhodopsin Kinase -> Phosphorylated Rhodopsin Tail (Serine) -> Reduced Gt Activation + Arrestin binding to Phosphorylated Rhodopsin -> Further Gt activation Reduction -> RGS Binds Transducin -> Transducin Hydrolysis of GTP (GAF) -> Inactive Transducin.
What is does RGS stand for?
Regulation of G-Protein Signalling. It is a protein.
What is the role of Ca2+ brought on by closed Ca2+ in repolarization of Visual Transducers?
The drop in Ca2+ levels brought on by closed Ca2+ channels, causes activation of Guanylyl Cyclase which raises cGMP concentrations restoring the cell to normal.
What sort of system is the restoration of a Visual Transducer and example of?
Why is negative feedback important to light sensitive cells?
It helps them to adapt to changing light conditions.