L23 Flashcards
where is ADH produced
• Vasopressin produced in the hypothalamus in the suber optic and paraventricular nuclei
where is ADH stored and released from
posterior
pituitary gland
what receptor does vasopressin bind to/where is the receptor
• Vasopressin binds to the vasopressin receptor (V2) on the basolateral membrane of LDT and CD cells
what is the result of ADH binding to the V2 receptor
• Results in incorporation of AQP2 channels into the apical membrane = increase H2O flow
what is diabetes insipidus
large volumes of urine
where is AQP2 located in the late distal tubule and collecting ducts
• apical membrane or
subapical cytoplasmic
vesicles
what is AQP2 regulated by
• AQP2 is regulated by the action of vasopressin (ADH)
when is the LDT and CD permeable to water
only in the presence of vasopressin
what is the membrane shuttle hypothesis
when things are stored in vesicles under the membrane, which then insert themselves into the membrane when needed (phosphorylation)
what happens intracellularly when ADH binds to the V2 receptor
it activates adenylyl cyclase which converts ATP-> cAMP which activates PKA
PKA phosphorylates the vesicles and AQP2 gets inserted into the apical membrane
what are some symptoms of diabetes insipidus (DI)
theres 5
- Polyuria - large volume - hypotonic urine (>15L/d)
- Polydipsia - excessive drinking
- First year of life - vomiting, fever, slow growth, developmental delay
- Severe dehydration
- Severe cases - mental deficiency due to dehydration of the brain
there are 2 types of DI. what are these
- Central Diabetes Insipidus (Neurogenic DI)
* Nephrogenic Diabetes Insipidus
what is Central Diabetes Insipidus (Neurogenic DI)
• Central Diabetes Insipidus (Neurogenic DI) - lack of production of vasopressin (ADH) by the hypothalamus or release from the posterior pituitary gland
what is Nephrogenic Diabetes Insipidus
- problem at the level of the kidney
They have lots of ADH but there is no response
what causes nephrogenic DI
there are 2 reasons
it is either the receptor (V2) or the channel (AQP2)
Congenital X-Linked NDI is a mutated V2
receptor
– 90% of NDI patients
– Normally males (because it is X linked)
• Autosomal NDI - mutated AQP2 channel
– 10% of NDI patients
– Normal V2 function
Congenital X-Linked NDI is a mutated V2
receptor. how many mutations are there in this receptor
200 especially located at the n terminus
Autosomal NDI - mutated AQP2 channel
44 of 53 mutations
what are the NAP boxes in the autosomal dominant NDI
NAP are made up of an asparagine, proline and alanine. These amino acids are within the 4 subunits which produce the pore itself which leads to improper function of the AQP2
mutations in V2 receptor and AQP2 result in…
5 problems
- non-functional AQP2 channels and V2 receptors
- ineffective biosynthesis of protein (AQP2 or V2) they will never get to the membrane as the golgi will detect that they are mutated and degrade them
- simple binding impairment of V2 receptors
- intracellular trafficking problems (AQP2 or V2)
- accelerated degradation of AQP2 channel or V2 receptor to the proteasome or lysosome
Which of the following statements is TRUE?
A. Vasopressin is produced in the supraoptic and paraventricular nuclei of the posterior pituitary gland.
B. Central diabetes insipidus is a problem with vasopressin
production, storage and release from the hypothalamus
C. Nephrogenic diabetes insipidus (NDI) is a problem at the
level of the late distal tubule and collecting duct.
D. Individuals with NDI exhibit reduced urine production.
A. is wrong as it says produced in the posterior pituitary. it is produced in the hypothalamus and stored/released from the posterior pituitary
B. it is only a problem with the release
D. increased urine production
C is correct
what is Bartters syndrome
it is autosomal recessive disorder which effects about 1:50,000 to 1:100,000 births
• salt-wasting (NaCl loss in urine)
what are some symptoms of Bartters syndrome
- hypereninism and hyperaldosteronism
- metabolic alkalosis
- hypokalemia (low blood K+)
there are 3 thypes of barters syndrome. what are their causes
• Bartter’s Syndrome Type 1
– apical Na+-K+-2Cl- cotransporter (NKCC2)
• Bartter’s Syndrome Type 2
– apical K+ channel (ROMK1)
• Bartter’s Syndrome Type 3
– basolateral Cl- channel (CLCNKB)
what part of the nephron does bartters syndrome effect the most
why
the thick ascending limb
because the role of this segment is to reabsorb Na, K and Cl
the TAL reabsorbs 25% of the Na filtered load
what is the effect of barters syndrome type 1
BS1 means that NKCC2 is impaired. This itself imparis ROMK1 which impacts the paracellular transport of Na, Mg and Ca
what is the effect of barters syndrome type 2
In BS2 these is a mutation on the tryosine (Y60X) of ROMK1 therefore even through you have a functional NKCC you mess up the K greident therefore everything stops working
what is the effect of barters syndrome type 3
BS3 is a mutation of the chloride channel which means that the cl conc inside the cell will increase which impears NKCC
what do mutations of NKCC2, ROMK1 and CLCNKB lead to
- non-functional channels or co-transporters
- ineffective biosynthesis of protein
- simple binding impairment of NKCC2
- intracellular trafficking problems
• accelerated degradation of the channels or
co-transporters
Which of the following statements is TRUE?
A. Bartter’s Syndrome Type 3 (BS3) is a problem with the Distal tubule.
B. BS patients exhibit hyporeninism and
hypoaldosteronism.
C. BS1 patients have a mutations of the Na-K-2Cl
cotransporter.
D. BS3 patients exhibit hyperkalemia
A. thick ascending limb
B. should say hypER not hypO
D. hypO not hypER
C is correct
what are the symptoms of liddles syndrome
theres 4
• hypertension due to increased Na+
reabsorption
- hypokalemic metabolic alkalosis
- pseudoaldosteronism (The reabsorption of Na is not because of aldosterone or renin therefore it is not a body response )
- suppressed levels of aldosterone and renin
normally under the presence of aldosterone Enac is inserted into the membrane so that Na is absorbed
in liddles syndrome what is happening in the principal cells
Principal cell
Liddell’s syndrome is when the ENaC is kept in the membrane, you then get more K entering the cell because of the Na/K ATPase which means that you get more Na reabsorbed and more K lost
in liddles syndrome what is happening in the intercalated cells
Intercalated cell
intercalated and principal cells are not separated
The principal cell causes the lumen to become negatively charged which causes the amount of H being lost from the body to increase
Water and CO2 (+ carbonic anhydrase) = bicarbonate causing metabolic alkalosis
what is the reason for liddles syndrome symptoms
principal cell
• Increased Na+ reabsorption leads to increased negative (-) luminal voltage
• This leads to increased K+ secretion
• Hence, hypokalemia (low blood K+)
intercalated cell
• The increased luminal negative voltage causes H+ secretion and HCO3- recycling by the intercalated cells
• Hence, metabolic alkalosis (increase H+ loss and gain of HCO3-)
Why is there increased Na+ reabsorption by the CD in patients with Liddles Syndrome?
Because of the subunits of the channel
describe ENaC (subunit)
- a, b, g subunits to make a functional channel
- PY motifs on C-termini-protein-protein interactions (P= proline, Y = Tryosine)
they have proline rich domains
what is the role of Nedd42
• Normally, Nedd-4-2 leads to an increase ubiquitylation of
ENaC; which tags ENaC to be removed from the apical membrane and targeted for degradation
R566X of b subunits of ENaC suggested that a portion of the C-terminus might be
important in regulating ENaC activity
X is a stop codon
what happens when there is a mutation at the C terminus of the ENaC channel
• mutations in the COOH terminus of ENaC causes the channel to remain at the membrane indefinitely!
when ENaC stays in the membrane indefinitely what does this cause
(3 things)
- this leads to hyperabsorption of Na+ with increased secretion of K+
- causes hypokalemia and metabolic alkalosis
- hyperabsorption of Na+ causes hypertension
Which of the following statements is FALSE?
A. Liddle’s Syndrome patients have hypokalemia.
B. The number of ENaC channels at the apical membrane are
increased in patients who have Liddle’s Syndrome.
C. In Liddle’s Syndrome, patients have hyperaldosteronism.
D. The R556X mutation of ENaC results in too many ENaC channels at the apical membrane of cells of the Collecting
Duct.
C is false as it should say hypO
