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(1-5) Translational Medical Science COPY > Trigger 3: Kidney ion channels and Gordon's disease mechanism > Flashcards

Trigger 3: Kidney ion channels and Gordon's disease mechanism Flashcards

1
Q

name three electroneutral cation chloride cotransporteds

A

NCC, NKCC2 and KCC

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2
Q

NCC

A

sodium chloride co-transporter

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3
Q

NKCC

A

sodium-potassium chloride co-transporter

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4
Q

KCC

A

potassium chloride cotransporter

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5
Q

NCC located

A

apical membrane of DCT cells (end of nephron near collecting duct)

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6
Q

DCT

A

distal convoluted tubule

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7
Q

percentage of NaCL reabsorbed within the DCT by NCC

A

5-10%

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8
Q

NKCC2 location

A

thick ascending loop of Henle (right hand side on diagram)

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9
Q

KCC location

A

proximal tubule (beginning of nephrite_

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10
Q

NKCC2 in the loop of hence absorb how much filtered NaCL

A

15-20%

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11
Q

electroneutral cation chloride cotransporters

A

define final salt conc i urine, affect blood volume and arterial pressure.

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12
Q

electroneutral cation chloride cotransporters can be medically inhibited by

A

thiazide-type diuretics

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13
Q

nephrons filters

A

20% of blood pumped from he heart (180L per day)

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14
Q

how much salt is reabsorbed b the nephron

A

99%

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15
Q

What does WNK stand for

A

‘with no K (lysine) protein kinase)

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16
Q

what are WNK

A

a family of protein kinases which comprise four members (WNK1, WNK2, WNK3, WNk4)

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17
Q

mutations in genes encoding…. and …. can be the cause of PHA2 (Gordon’s)

A

WNK1 and WNK2 and KLHL3/CUL3

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18
Q

catalytic domain of WNK1

A

N terminus residues 221-479

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19
Q

catalytic domain of WNK4

A

N terminus residues 174-432)

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20
Q

which other complex can have mutations which cause Gordon’s?

A

CUL3-KLHL3 complexes

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21
Q

which signalling pathway phosphorylates NCC causing it to open and draw in sodium

A

WNK1-SPAK/OSR1 kinase signalling

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22
Q

where is SPAK expression localised to?

A

the TAL (thick ascending loop) and the DCT

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23
Q

which protein needs to be phosphorylated to activate NCC activity

A

Thr60

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24
Q

A protein kinase …

A

is an enzyme which modifies other proteins by adding phosphate groups to them (phosphorylation)

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25
Q

the human kinome

A

the part of the genome which encodes kinases (500 protein kinase genes)- around 2% of the

26
Q

up to …% of human proteins may be modified

A

30%

27
Q

WNK kinases make up a unique branch of the human kinome… most closely related to the

A

STE KINASES

28
Q

OSR1 and SPAK are part of the

A

protein kinase family

29
Q

Woks are …. proteins, consisting of how many aa

A

large- 2126 aa

30
Q

what anchors and orientates ATP in WNKs

A

lysine at the N terminus (K233)

31
Q

what does WNK1/4 do to SPAK and OSR1

A

phosphorylates and activate.

Activation is mediated by T-loop phopshorylation

32
Q

relationship between SPAK and OSR1

A

68% identical in sequence and possess highly similar (90%) catalytic domain

33
Q

WNKs do not

A

phosphorylate NCC directly

34
Q

what type of protein kinase is SPAK?

A

Step20p-related protein kinase

35
Q

WNKs do not phosphorylate NCC directly… they interact with

A

SPAK/OSRR1 which phosphorylates NCCS

36
Q

when is WNK activated

A

in response to osmotic stress

37
Q

In response to osmotic stress what does WNK1 do

A

it phosphorylates and activates SPAK/OSR1 kinases. Which goes onto phosphorylate and regulate the activity of ion co-transporters smh as NCC

38
Q

Ubiquitination is an

A

enzymatic post-translation modification in which ubiquitin protein is attached to a substrate protein–> sends for destruction in the proteasome

39
Q

outline the ubiquitination system

A

1) ubiquitin is activated by E1 (ubiquitin -activating enzyme)
2) Ub is then transferred to E2 (ubiquitin carrier protein)
3) E3 ligases bind to target substitute and coordinate covalent attach meant of Ub (from E2)
4) target protein may be monoubiquitinated or polyubiquitinated
) sent to the proteosome for proteosomal destruction

40
Q

WNK is a substrate for which complex

A

CUL3-KLHL3

41
Q

CUL3-KLHL3

A

ubiquitinates WNK1/4, meaning it is sent for proteosomal degradation instead of phosphorylating SPAK/OSR1- therefore less NCC channels are activated

42
Q

Normal process

A

Osmotic potential is normal, there CUL3/KLHL3 ubiquitinates WNK4, sending it for degradation in the proteasome. Therefore SPAK/OSR1 is only lightly activated and not many NCC channels are activated - maintaining balance

43
Q

PHAII process

A

Mutation in WNK4 or CUL3/KLHL3 prevents degradation of WNK4, therefore there are many WNK4 to phosphorylate SPAK/OSR1- therefore powerful activation of NCC

44
Q

what are the mechanisms that contribute to the development of Gordon’s syndrome (1-4)

A
  • genetic modification (e.g. WNK1/4 and CUL3/KLHL3)
  • protein phosphorylation (activation)
  • protein ubiquitylation (protesomal degradation)
  • ion homeostasis
45
Q

activated WNk kinases bind to SPAK to phosphorylate them where

A

Thr243

46
Q

activates SPAK will then bind to NCC and phosphorylate at

A

Thr60

47
Q

pNCC

A

has increased intrinsic activity and increases Na influx

48
Q

where is the catalytic lysin in WNK family members locacted

A

the glycine-rich B strand 2, rather than the normal position in B strand 3 of the kinase domain

49
Q

How are WINK PK different to other PKs

A

catalytic lysine is found in glycine-rich b strand 2,rather than 3 of the kinase domain

50
Q

chloride sensing by WNK1 involves

A

inhibition of autophoshorylation

51
Q

NKCC1 causes what to end the cell

A

Na, K and 2Cl-

52
Q

NCC causes what to end the cell

A

Na, Cl

53
Q

NKCC2 causes what to end the cell

A

Na K 2 Cl-

54
Q

WNK4 has how many exons

A

19

55
Q

all pathogenic variants for WNK4 are

A

missense

56
Q

all pathogenic variants in WNK4 have been identified in exons

A

7 and 17

57
Q

relationship between metabolic acidosis and potassium

A

Renal acid secretion is influenced by serum K+ and may result from the transcellular shift of K+ when intracellular K+ is exchanged for extracellular H+ or vice versa. In hypokalemia, an intracellular acidosis can develop; in hyperkalemia, an intracellular alkalosis can develop.

58
Q

ROMK channels

A

an ATP-dependent potassium channel

59
Q

Mutations in WNK4 are missense mutations and cause

A

loss of function, so that WNK4 loses its ability to suppress NCCT and ROMK.

60
Q

ROMk is predominantly expressed in

A

thick ascending limb and cortical collecting duct.

61
Q

how CUL3/KLHL3 regulates WNK1/4 pathway

A

1) E1 becomes activated by ATP, with the addition of a Ub
2) E1 transfers Ub to E2
3) E2 is recruited to E3 which is complexed with the substrate (e.g. WNK)
4) Ub transferred to substrate
5) process repeats until WNK is ubiquitinated enough to be sent for proteasomal degradation

62
Q

CUL3 has ……

A

E3 ubiquitin ligases

(1-5) Translational Medical Science COPY (21 decks)

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