Lecture 10 Flashcards
Briefly describe the cellular signalling/signal transduction pathways in epithelia
There is a stimulus which causes a ligand to be released. This binds to the receptor in the membrane or intracellularly. There is signal transduction through a 2nd messenger or other wats. We then need to be able to turn it off and so there is negative feedback
Where are receptors location and what sorts of things bind to them?
Water soluble ligands bind to plasma membrane receptors and lipid-soluble ligands bind to cytoplasmic or nuclear receptor
What is an example of a lipid soluble ligand that binds to a receptor inside the cell?
a steroid
Lipid soluble ligands tend to alter what?
they alter gene expression
Which is faster at causing an effect, water-soluble or lipid-soluble ligands. Why is this?
The water soluble ones because lipid soluble ligands alter gene expression and so there needs to be time for the genes to transcribe, translate and for there to movement of the required genes
Briefly describe G-protein coupled receptors
There is a receptor and a G-protein which is made up of an α, β, and γ subunit. When the ligand binds to the receptor, the G-protein becomes associated with the receptor. GTP is converted to GDP and then there is dissociation of these subunits and they can go off and do stuff
What is the function of the kidney?
it filters blood removing wastes and extra water to make urine
What does the kidney control?
blood pressure
What are the three main hormones that regulate NaCl and water transport pathways in the kidney tubules?
- angiotensin II and aldosterone
- atrial natriuretic peptide (ANP)
- antidiuretic hormone/vasopressin
What is the purpose of angiotensin II and aldosterone?
to increase the NaCl and water reabsorption to increase blood pressure
What is the purpose of atrial natriuretic peptide?
to decrease NaCl and water reabsorption
What is the purpose of antidiuretic hormone/vasopressin?
to mainly increase water reabsorption
Briefly describe the angiotensin II signal transduction in the adrenal cortex stimulating aldosterone release
In response to a low blood pressure, angiotensin || acts on the adrenal glands which release aldosterone which causes an increase in the Na+ uptake from the kidney tubules and increase blood pressure
What stimulates angiotensin II signal transduction in the adrenal cortex?
low blood pressure
Describe the angiotensin II signal transduction in the adrenal cortex
In response to low blood pressure (sensed via low perfusion pressure in the kidneys and a decrease in NaCl to the macula densa) renin is released from the kidneys and this cleaves angiotensinogen (from the liver) to form angiotensin I which is further cleaved by ACE to form angiotensin II. Angiotensin II binds to the AT1 receptor on the zona glomerulosa cells of the adrenal cortex
How does the kidney know that there is low blood pressure?
there is low perfusion pressure in the kidneys and a decrease in NaCl to the macula densa
What is released from the adrenal cortex when angiotensin II binds?
aldosterone
Explain how the binding of angiotensin II to the AT1 receptor of the zona glomerulosa in the adrenal cortex occurs
The AT1 receptor is a GPCR with a G-protein complex associated with it. When angiotensin II binds to this receptor, there is release of aldosterone which has effects on the cortical collecting duct of the kidney to cause Increase Na+ uptake from kidney tubules and increase blood pressure
Where does aldosterone have effects?
on the cortical collecting ducts of the kidney
Describe the angiotensin II signal transduction in the adrenal cortex
In response to low blood pressure (detected as low perfusion pressure in the kidneys and a decrease in NaCl to macula densa), renin is released from the kidneys which cleaves angiotensinogen to angiotensinogen I. This is further cleaved by ACE to angiotensinogen II. This binds to the AT1 receptor on the zona glomerulosa cells of the adrenal cortex
Where is angiotensinogen released from?
The liver
Describe what happens when angiotensin II binds to the AT1 receptor in the zona glomerulosa cells
The AT1 receptor is an GPCR so when angiotensin II binds to the receptor, the g protein dissociates and the α subunit interacts with phospholipase C. This breaks down PIP2 to IP3 and DAG which increase aldosterone levels. DAG activates PKC which helps with the synthesis of aldosterone. IP3 binds to IP3R3 in the ER and this releases Ca2+ from the ER and this drives aldosterone synthesis and release from the adrenal cortex
Angiotensin II binds to its receptor in the plasma membrane BECAUSE angiotensin II is a lipid-soluble ligand
true, false
Is aldosterone a lipid soluble molecule? Why or why not?
Yes because it is a steroid hormone
Describe how lipid soluble molecules get into the cells and what they do once in there
Because it is lipid soluble, it diffuses into the cell. It binds to its intracellular receptor to form a receptor complex. This goes into the nucleus to activate primary response genes which act to do two things.
What are the two different things that primary response genes do when they are activated by the aldosterone-receptor complex?
- turn on secondary response genes
2. shut off further expression of primary response genes in negative feedback
Describe how aldosterone molecules get into the cells and what it does once it is in there
Because it is lipid soluble, aldosterone diffuses into the cell. It binds to its intracellular receptor called MR to form a receptor complex. This goes into the nucleus to activate the transcription of SGK genes
What is the purpose of the SGK gene?
2
- It decrease the ENaC (epithelial Na+ channel in the apical membrane) endocytosis ie. stops it being retrieved from the membrane, and degradation which means that ENaC that is already at the membrane will stay there. This means Na+ can come down its concentration gradient from the apical membrane (urine) into the cell
- it also promotes transcription of secondary response genes (ENaC)
What is the overall effect of the SGK gene?
Both of the purposes lead to an increase in the Na+ transport, increased Na+ in the ECF, water retention and thus an increase in blood volume and blood pressure
How can we switch off the angiotensin II signal transduction when the blood pressure is back to normal?
When BP is back to normal, there is no renin released and so angiotensinogen remains so there is less angiotensin I and hence angiotensin II levels decrease. Even if there was angiotensin II around, the receptors are endocytosed so there is no receptor for it to bind to. There is an activation of GTPase in glomerulosa cells so if any GTP is made, it gets converted back to GDP. If this doesn’t work, we get increased expression of Ca2+ pump of the ER so Ca2+ goes back into the ER so there is no aldosterone expression
If blood pressure gets too high, ________ can be released
ANP
The ANP receptor is what kind of receptor?
an enzyme linked receptor
What happens when ANP binds to its enzyme-linked receptor?
The receptor contains guanylyl cyclase which catalyses GTP to cGMP and the increase in cGMP activates PKG. PKG phosphorylates Na+/K+ ATPase on the basolateral side to decrease its activity which means that Na+ is not pumped out of the cell. This means that there is no osmotic gradient so no H2O comes in so there is a decrease in blood pressure and blood volume
Where is ANP released from? What is this in response to?
If there is an increase in blood pressure, the atria stretch more which causes ANP to be released from cells in the heart which then bind to receptors
How can we stop the release of ANP?
Phosphodiesterase converts cGMP to GMP which means that cGMP can’t activate PKG. If there is less stretch, there is less ANP being released ad so there is endocytosis of the ANP receptor so it can’t bind to ANP to start the signal transduction pathway
What is released when we are dehydrated?
ADH/vasopressin
Describe what happens when ADH binds to its receptor
ADH binds to its V2 receptor (a GPCR). This activates a G-protein and this activates adenylyl cyclase. This catalyses the conversion of ATP to cyclic AMP so the levels of cAMP increase. This increase in cAMP activates PKA which phosphorylates an aquaporin 2 channel which normally sit in vesicles in the cell but once phosphorylated, they move to the membrane. This increase the H2O absorption from the urine and then it gets into the blood through aquaporin 3 or 4
Where is ADH released from?
the posterior pituitary gland
When is ADH released?
In response to ECF osmolarity increase
How can we turn off the ADH signalling pathway when we drink too much water?
There is no ADH/AVP released from the posterior pituitary gland when the ECF osmolarity is back to normal. The V2 receptor is endocytosed so there is no cAMP increase, PKA is inactive, AQP2 is not phosphorylated and there is less water reabsorption
