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Molecular And Cellular Pharmacology > Pharmacological Modulation Of Katp Channels > Flashcards

Pharmacological Modulation Of Katp Channels Flashcards

1
Q

What type of channel is a Katp channel?

A

Inward rectifying K+ channel

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2
Q

What does inward rectifying mean? How does it apply to the Katp channel

A

Favours ion influx over efflux
Voltage current relegation ship does not follow ohms laws. However, since Ek is approx -80mV, at physiological potentials K+ still moves out of cell

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3
Q

Why is influx favoured over efflux for Katp channels?

A

Efflux is blocked by intracellular contents such as polyamines e.g. Spermine

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4
Q

What are polyamines?

A

Cytoplasmic long chain aliphatic compounds with more than one amine group
The positive charge permits binding to proteins

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5
Q

What subunits form the Katp channel?

A

4 pore forming regions (Kir)

4 regulatory subunits which are sensitive to atp and therefore metabolic state of cell

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6
Q

Structure of Kir6.1 and 6.2 subunit?

A 
Intracellular N terminus
TM1
P loop
TM2
Intracellular c terminus
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7
Q

Are Kir channels voltage sensitive?

A

No

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8
Q

What associates with Kir subunits?

A

Sulphonylurea receptor subunit

Regulatory subunit

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9
Q

What is the structure of the SUR?

A

Receptor subunit split into 3 discrete transmembrane sections consisting (TM0, TM1 and TM2) of 5, 6 and 6 membrane spanning segments respectively

Extracellular N
TM0
Intracellular linker between TM0 and TM1 (L0)
TM1
Intracellular linker between TM1 and TM2 (L1) contains NBD1
TM2
Intracellular C terminus with NBD2

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10
Q

Where is the important interaction for Kir 6.2 and SUR?

A

Cytoplasmic N terminus of kir6.2 and TMD0 and L0 linker important for channel gating by SUR

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11
Q

Name some drugs which bind to the sulphonylurea regulatory subunit

A

Gliclazide
Tolbutamide
Glibenclamide

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12
Q

What hypoglycaemic drugs act at Katp channels?

A

Sulphonylureas

Meglitinides

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13
Q

ADRS of sulphonylureas

A

Manly weight gain and hypoglycaemia

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14
Q

What do sulphonylureas do at the Katp channel?

A

Block it
I.e. Close the channel causing cell to depolarise and release insulin in the same way rising glucose causes insulin release

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15
Q

Where do the 4 pore forming subunits and the 4 regulatory subunits co assemble?

A

In the ER.

Then inserted into the membrane

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16
Q

The channels are sensitive to low levels of intracellular ATP. What happens when ATP binds?

A

The channel closes

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17
Q

What ratio reflects the metabolic state of the cell?

A

ADP to ATP ratio

Will govern receptor open probability

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18
Q

What is the effect of ADP for channel function?

A

Stimulates channel to remain open

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19
Q

Where is the ATP binding site?

A

Located on both the Kir 6 and SUR subunit

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20
Q

What other factors modulate Katp channel activity?

A

Level of phosphotidylinositol 4,5 bisphosphate
Increase in PIP2 increases activity (increases open probability and decreases ATP sensitivity) therefore contents of memebrane important. PIP2 cleavage by PLC will regulate channel activity

Acidic intracellular environment also stimulates activity

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21
Q

What gene encodes for Kir 6.1

A

KCNJ8

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22
Q

What gene encodes for Kir 6.2?

A

KCNJ11

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23
Q

What gene encodes for SUR1?

A

ABCC8

24
Q

What gene encodes for SUR2a and SUR2b?

A

ABCC9 (alternative splicing)

25
Q

Where is Kir 6.1 found?

A

Ubiquitous

26
Q

Where is Kir 6.2 found?

A

Pancreatic beta cells
Brain
Heart
Skeletal muscle

27
Q

Where is SUR1 found?

A

Pancreatic beta cells

28
Q

Where is SUR 2A and 2B found?

A

2A Heart and brain

2B smooth muscle

29
Q

What is the combination of subunits in pancreatic beta cells?

A

Kir6.2/SUR1

30
Q

What is the combination of subunits in vascular smooth muscle cells?

A

Kir6.1/SUR2B

31
Q

What do fluorescence studies using FURA2 of pancreatic beta cells show?

A

Membrane potential in couple to calcium influx

Aguilar-Bryan et al 1999

32
Q

What does sulphonylureas do to membrane potential?

A

Cause a depolarisation and action potentials

33
Q

Who conducted the study which showed what subunit area in Katp channels regulates sulphonylurea selectivity?

A

Ashcroft et al 1999

34
Q

What subunit is more selective for tolbutamide?

A

SUR1>SUR2

35
Q

How can the difference in selectivity be used to find the tolbutamide binding site?

A

Create chimeric proteins through joining genes for SUR1 and SUR2. Creates a protein with functional properties derived from each original protein.
Since SUR2 tolbutamide selectivity is weaker than SUR1 a chimer where the SUR2 subunit section replaces the respective SUR1 subunit section for which tolbutamide binds will show an increase in conductance. This is because it is not blocked by tolbutamide.

The opposite could be done whereby SUR1 subunit section inserted into SUR2 subunit at area where tolbutamide will bind will show an increased selectivity to tolbutamide

36
Q

What areas is essential for tolbutamide binding?

A

TMD2 (the areas on the 14th and 15th membrane spanning domain and the distal part of ICL7 and proximal ICL8)

37
Q

For modulating Katp channels why do we want a high selectivity for kir6.2/SUR1 relative for other channel subtypes?

A

To avoid possible cardiac ADRS
E.g. Cardiac muscle has kir6.2/SUR2A
We want drug which has a greater affinity for beta cells

38
Q

What two conditions arise from Katp channel mutations?

A

Permanent neonatal diabetes

Hyperinsulinaemic hypoglycaemic of infancy

39
Q

What is permanent neonatal diabetes and what mutations cause it?

A 
Diabetes diagnosed within 6 months of birthed that does not resolve 
1:260000 levels births
30% Kir6.2
20% SUR1
50% other e.g. Glucokinass
40
Q

What are the two types of permanent neonatal diabetes?

A

Mild - caused by mutation in binding site

Severe - caused by a gating mutation

41
Q

What kir6.2 causes mild PND? And it respond to sulphonylureas?

A

R201H/C mutation in ATP binding site
Decreases sensitivity to ATP (more atp needed to decrease channel conductance)
Channel favours open state
Yes it does respond to sulphonylureas

42
Q

What mutations causes severe PND?

A

Mutation in KCNJ11 (Q52R or I296L)

Mutation in ABCC8

43
Q

What condition is severe PND associated with?

A

Developmental delay, epilepsy and neonatal diabetes (DEND)

Associate with kir6.2 gating mutations nd some ABCC8 mutations

44
Q

What is the effect of severe PDN with kir6.2 mutations on channel function?

A

Channel is favours open probability independent if ATP concentrations problem with channel gating (not ATP sensitivity) not responsive to sulphonylureas

45
Q

Severe PND caused by SUR1 mutations do what to Katp channel?

A

Overactive and channels do not responce to glucose metabolism
Memebrane remains hyperpolarise and no insulin release

46
Q

Does sulphonylureas work to treat PND caused by SUR1 mutations?

A

It depends where the mutation in SUR1 is so individual molecular diagnosis is needed

47
Q

Hyperinsulinaemic hypoglycaemic of infancy (HHI) is due to what mutations?

A

Kir6.2
SUR1 (50%)
There’s mutations mean channel is not working and thus memebrane releases depolarised and increases insulin release

48
Q

Prevalence of HHI?

A

1: 50000
1: 3000 in areas if high consanguinity

49
Q

Class 1 HHI is caused by what?

A

Protein trafficking defect so no channel at membrane

This is severe

50
Q

Class 2 HHI is characterised by what?

A

Functional channel mutation (normally in SUR1) which causes channel to remain closed and decreased effect of ADP to open channel
It is mild in nature

51
Q

How can we treat class 2 HHI?

A

K+ channel openers - diazoxide
However, to treat a functional Katp channel is needed
Mutations which cause structural channel changes may not be as responsive to diazoxide

52
Q

Name some K+ channel openers - why may they be used for cardiovascular disease?

A

Diazoxide
Minoxidil
Nicorandil
Vascular SM contains kir6.1/SUR2B therefore openers will cause vasodilation

53
Q

What is diazoxide used for and what SUR subunits does it work on?

A

Hypertensive crisis and HHI

SUR1 and SUR2B

54
Q

ADRS of diazoxide?

A

Hyperglycaemia
Hirsuitism
Hypertrichrosis

55
Q

What is nicorandil used for? Name an ADR

A

Angina (NO Donor + Katp channel opener)

GI ulceration

56
Q

What is another use of Katp channel openers?

A

Ischaemic preconditioning

Opening K+ channels mimic ischaemia and decreases AP duration and makes them less likely to fire

Molecular And Cellular Pharmacology (12 decks)

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