Beta 2 Adrenoreceptor Regulation Flashcards
(45 cards)
When adrenaline is circulating the body is comes into contact with with what receptors specifically in the liver and skeletal muscles?
Beta 2 adrenoreceptors
These are G protein coupled receptors!
What do beta 2 adrenoreceptors in the body do? What are they coupled with? And what pathway do they activate
They detect adrenaline
They provide the bodies muscles with the energy to contract needed in a fight or flight scenario
Remember These beta 2 adrenoreceptors are G protein coupled receptors
The receptor is coupled with alpha and beta G protein sub units
The adrenoreceptor sends signals to the alpha subunit it is ATTACHED to. This then allows a signal to pass through the Gs pathway! The receptor’s alpha sub unit becomes ACTIVATED>
So what happens when adrenaline binds to beta 2 adrenoreceptors?
And remember these receptors are G protein coupled receptors
When the adrenaline binds it causes a signal to be sent from the receptor to the alpha sub unit the receptor is bound to
On the alpha sub unit this causes a GTP to bind which is exchanged for a GDP.
When the GTP is BOUND to the alpha sub unit … the alpha and beta subunits can DISSOCIATE from each other and the receptor
These sub units can go onto work on downstream effectors
When happens when the alpha sub unit from the receptor dissociates?
The alpha sub unit becomes activated. This is referred to as the stimulatory G alpha S sub unit
This works on the enzyme adenylate cyclase
This produces a second messenger cyclic AMP which works further downstream
How does the beta 2 adrenoreceptor and the work of adenyl cyclase allow for signal amplification?
Remember this receptor is G protein coupled and works when adrenaline binds to it.
- while the beta 2 adrenoreceptor has an agonist bound it can activate multiple G proteins
While the alpha sub unit (the stimulatory G alpha S protein) is bound to adenyl cyclase, it allows for lots of cyclic AMP to be made
This is amplification!
What does cyclic AMP do once it has been produce by adenyl cyclase after the GTP bound alpha S subunit from the adrenoreceptor has bound?
It associates with regulatory subunits found on protein kinase A
This causes the regulatory sub unit bound to the kinase to LEAVE the kinase
The kinase then becomes ACTIVATED
What happens once the CAMP activates protein kinase A?
This kinase A then uses the energy of ATP to phosphorylate other kinases such as calmodulin phosphorylase kinase.
What does calmodulin phosphorylase kinase do?
Note this is activated by kinase A
So once ACTIVATED This kinase is sensitive to intracellular levels of calcium and calcium which binds to calmodulin
The phosphorylation of this calmodulin P Kinase lowers it sensitivity to the calcium
This means it can become ACTIVATE (as in the kinase has activated it already and thus it is ready to become active) at lower levels of calcium
The role of this enzyme is to phosphorylate the enzyme phosphorylase P
What does the enzyme phosphorylase P do?
Remember protein kinase A phosphorylates and makes calmodulin phosphorylase kinase become ACTIVATED
This calmodulin kinase then phosphorylates enzyme phosphorylase P
This enzyme metabolises the conversion of gylcogen to glucose 6 phosphate
This allows glucose 6 phosphate to be cleaved off of glycogen
This provides the energy in the liver and skeletal muscles for contraction. Via the production of ATP via glycolysis.
Again what does the beta 2 adrenoreceptor do?
It responds to adrenaline
It activates a g protein
This g protein activates adenyl cyclase which produces cAMP. This cAMP is used to activate protein kinase A, then calmodulin phosphorylase kinase. This calmodulin remains activated until it detects calcium (low levels can be sensed due to phoshphorylation of kinase A)
This then is activated activating phosphorylase P.
This phosphorylase helps break down glycogen into glucose 6 phosphate
This is then broken down to provide the energy for muscle contraction.
What are the two ways in which signalling from the beta 2 adrenoreceptor is limited?
(Note this would stop glucose metabolism from THIS pathway and stop muscle contraction in response to adrenaline)
- GTPase action on the alpha sub unit can cause the GTP bound G alpha protein to then become GDP bound. In this form the alpha sub unit can no longer bind to the adenyl cyclase.
- The beta arresting kinase can stop further signalling.
How does the beta arresting kinase work? Which of the g protein sub units does it work with from the original beta 2 adrenoreceptor G protein complex?
(Note it acts as a negative feedback system)
When the beta 2 adrenoreceptor has been under prolonged stimulus the BETA gamma subunits which has detached from the original G protein coupled receptor complex goes onto recruit a receptor kinase
This kinase phosphorylates the carboxyl terminus of the beta 2 adrenoreceptor
This attracts a protein called beta arresting
This stops signalling to the alpha sub unit of the complex
Note: this happens after some time! In effect the receptor becomes DESENSITISED overtime!
The receptor no longer responds to the prolonged stimulus.
What does the G alpha Q protein do?
(Note this G protein is not exclusive to the beta 2 adrenoreceptor as it works on other G protein coupled receptors!
It controls the activity of phospholipase C which is a lipase that breaks down lipids
These types of second messengers are derived from membrane lipids
The breakdown of these membrane lipids create second messengers like IP3 and DAG
NOTE beta gamma sub units may also have a similar role!
What receptors use Lipid derived signalling ?
Many!
For example the lipid derived messenger IP3 can interact with calcium, helping signalling from ligand gate ion channels for example.
What are the three types of lipid membranes broken down to make secondary lipid messengers? And what is the main one?
PIP2 - phosphatidylinositol 4,5 bisphosphate
PC
Sphingomyelin
What is the structure of PIP2 and what enzymes break it down into lipid derived second messengers?
(Remember cAMP is a type of second messenger too)
- this PIP2 is made up of phosphatic acid, diacylglycerol and IP3, arachidonic acid
These are important second messengers!
Enzymes such as phospholipase C, D and A2 are the main enzymes which break down this membrane phospholipid into second messengers
In particular what breaks down the bond between PIP2 and IP3? And what does the IP3 do?
Phospholipase C (remember this is regulated by G alpha Q proteins) breaks the phosphodiester bond between PIP2 and the IP3. This allows it to be liberated.
It can go onto affect effector proteins some distance away from its production
NOTE - phospholipase D can also liberate the IP3 but this causes the IP3 not to be a triphosphate! This causes the IP3 to be phosphatic acid instead!!
What is a good characteristic of the IP3 lipid derived second messenger?
It is hydrophilic - thus it dissolves well in the cytoplasm (it isnt scared of water)
What enzyme liberates DAG from PIP2? And whats a characteristic of DAG?
Phospholipase C
DAG is hydrophobic. It doesn’t dissolve in the water of the cytoplasm as well so it mainly stays around the plasma membrane.
What does phospholipase A2 do to PIP2, the membrane phospholipid?
It liberate arachidonic acid
And remember this is used by the COX enzymes attached to the ER in the cell, used for calcium signalling?
Summary of steps in lipid liberation to make lipid derived second messengers?
A receptor activates G alpha Q
This then liberates a G beta gamma sub unit from a G protein coupled receptor
(Remember these receptors typically have an alpha and beta sub unit)
This then act on phospholipases
By activating this enzyme, they generate a second messenger such as Ins P3 (IP3) or DAG
This regulates effector function downstream
The G alpha Q’s most common pathway involves the breakdown of PIP2 into DAG and IP3 which are second messengers. What do these second messengers do?
DAG the second messenger stimulates Protein kinase C (this is not the same kinase that activates calmodulin phosphorylase kinase, this is kinase A._
Kinase C works to phosphorylate proteins in the plasma membrane not in the G protein S pathway!!
IP3 woks on Ca2+ channels and IP3 receptor.
Note PI3 kinases can also break down PIP2 into protein kinase C pH domain proteins
Note - the enzymes involved in breaking down the phospholipids in the plasma membrane differ between different G protein pathways. However they all have the same properties
What are some similar properties?
They have similar catalytic domains which break down the phosphodiester bond which generates DAG and IP3
They all have regulatory domains
They have PH domains
Some have calcium binding domains - showing calcium binding is important
What class of enzyme does the G alpha Q protein work on and what part of the enzyme recognises it?
- the phospholipase C beta 1 -4 isoforms
- these enzymes have extended carboxyl terminals
These recognise the G alpha Q sub units
