L23 Flashcards by Hayley 1234

where is ADH produced

• Vasopressin produced in the hypothalamus in the suber optic and paraventricular nuclei

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where is ADH stored and released from

posterior

pituitary gland

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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

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what is the result of ADH binding to the V2 receptor

• Results in incorporation of AQP2 channels into the apical membrane = increase H2O flow

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what is diabetes insipidus

large volumes of urine

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where is AQP2 located in the late distal tubule and collecting ducts

• apical membrane or
subapical cytoplasmic
vesicles

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what is AQP2 regulated by

• AQP2 is regulated by the action of vasopressin (ADH)

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when is the LDT and CD permeable to water

only in the presence of vasopressin

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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)

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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

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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

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there are 2 types of DI. what are these

Central Diabetes Insipidus (Neurogenic DI)

* Nephrogenic Diabetes Insipidus

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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

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what is Nephrogenic Diabetes Insipidus

problem at the level of the kidney

They have lots of ADH but there is no response

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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

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Congenital X-Linked NDI is a mutated V2

receptor. how many mutations are there in this receptor

200 especially located at the n terminus

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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