NaV channels Flashcards

1
Q

at what mV is the NaV closed

A

-65

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2
Q

at what mV is the NaV open

A

-40

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3
Q

how is it selective towards Na

A

only allows Na+ ions to pass
ex - K+ ions are too large

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4
Q

how does the channel open

A

by depolarisation

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5
Q

how long do they stay open for, and what happens once they close again

A

~1msec, and then they become inactive and cannot be opened again

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6
Q

what happens in response to a membrane depolarisation

A

they open rapidly from a resting state

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7
Q

what happens when depolarisation is maintained

A

the Na+ channels exit open state and enter inactivated state

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8
Q

define whole cell current

A

individual channels open at different times, so this is ever changing

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9
Q

R =

A

resting (closed) state (favoured by hyperpolarisation)

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10
Q

O =

A

open state (transiently favoured by depolarisatoon)

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11
Q

I =

A

inactivated state (favoured by maintained depolarisation)

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12
Q

how many gates do Na+ channels have within axons

A

2

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13
Q

what are the 2 gates within axons called

A

activation gate and inactivation gate

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14
Q

describe the events of an action potential in a cell at the Na+ channels

A
  • at the resting membrane potential, the activation gate closes the channel
  • depolarising stimulus arrives at the channel and opens the channel
  • with activation gate open, Na+ enters the cell
  • inactivation gate closes and Na+ entry stops due to hyperpolarisation
  • during repolarization caused by K+ leaving the cell, the 2 gates reset to their original positions
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15
Q

what is activation of NaV channels dependant on

A

voltage

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16
Q

more depolarisation =

A

more sodium influx

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17
Q

the amount of Na+ current (i.e. proportional to number of open channels) is dependant on

A

the magnitude of the depolarisation

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18
Q

what is inactivation of NaV channels dependant on

A

voltage

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19
Q

the process of inactivation determines …

A

the number of Na+ channels avaliable to open at any given membrane potential

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20
Q

how many beta subunits are there

A

4 (beta1-beta4)

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21
Q

what is the difference between all the beta subunits

A

they have similar structures but are seperate proteins

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22
Q

what to beta protein subunits modulate

A

channel gating, allowing rapid activation and inactivation

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23
Q

what is a mutation in the beta1 subunit associated with

A

epileptic seizures

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24
Q

what do immunoglobulin domains thought do do

A

bind extracellular proteins and be important determinants of channel localisation in cells

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25
Q

what does the extracellular domain of both beta proteins possess

A

an immunoglobulin-like fold

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26
Q

how many sodium channel alpha subunit genes are there in the human genome

A

9 (NaV 1.1-1.9)

27
Q

what are the subunits that predominate in the CNS

A

Nav1.1, 1.2 and 1.3

28
Q

what are NaV 1.1-1.3 sensitive to

A

nM TTX

29
Q

what are the TTX-resistant isoforms and where are they found

A

NaV 1.8 and 1.9 - found in the peripheral NS

30
Q

what are the TTX-resistant isoforms expressed as

A

small-diameter dorsal root ganglion neurons (including C-fibres which transmit nociceptive pain)

31
Q

what are the TTX-resistant isoforms thought to sustain

A

repetitive firing of depolarised nerves

32
Q

what are TTX-resistant channels involved in

A

the pathophysiology of chronic inflammatory pain

33
Q

where are NaV 1.8 and 1.9 increased

A

in nerve fibres, proximal to site of injury

34
Q

what happens when expression of NaV1.8 is reduced

A

attenuated neuropathic pain and analgesic to noxious mechanical stimuli

35
Q

which alpha subunit is TTX sensitive

A

NaV1.7

36
Q

where are NaV1.7’s expressed

A

selectively in dorsal root ganglion neurons, particularly nociceptive cells

37
Q

what sets gain for pain in nociceptors (sets pain threshold)

A

NaV1.7

38
Q

what happens when mutations occur in NaV1.7 in mice

A

cause of primary erythromelagia an autosomal dominant, inherited disorderm severe burning sensation and redness in extremities in response to mild thermal stimuli

39
Q

what happens with mutations/loss of NaV1.7 in humans

A

unable to feel pain

40
Q

how do local anaesthetics prevent AP propagation of nerve axons

A

by blocking NaV channels

41
Q

what are LAs

A

small lipid soluble molecules and as such cross the nerve sheath and cell membrane to reach site of action

42
Q

what do LAs consist of

A

an aromatic group linked by an amide or ester bind to a basic side chain, and at physiolgical pH’s are usually charged (+)

43
Q

list some clinally useful LAs

A

procaine, lignocaine and bupivacaine

44
Q

why are permenantly charged derivitives of LAs ineffective

A

they are unable to penetrate nerve cell membranes

45
Q

what is the blocking action of LAs dependant on

A

the NaV channel being OPEN

46
Q

what else do LAs enhance

A

the NaV inactivation process (they stabilise it)

47
Q

what is tetrodotoxin (TTX)

A

a naturally occuring, virulent poison that blocks nerve conduction and causes death by respiratory paralysis

48
Q

where is TTX found

A

in internal organs of the pacific puffer fish

49
Q

what does TTX do

A

blocks NaV channels of nerves and skeletal muscle in nanomolar range - but cardiac NaV channels are much less sensitive (micromolar range)

50
Q

how does TTX work

A

blocks NaV channels from the outside of the cell
it binds to the AA residue on the outer mouth of the channel

51
Q

what does saxitoxin do (STX)

A

similar to TTX - blocks NaV channels from AA site on outside of cell

52
Q

where is STX found

A

produced by dinoflagellates (a unicellular organisms in marine plankton)

53
Q

what can STX cause if ingested

A

paralytic shellfish poisoning (which is often fatal)

54
Q

what are u-conotoxins

A

constituents of venom of the group of predatory molluscs - cone shells
they are positively charged peptides

55
Q

how do u-conotoxins work

A

they are injected into pray via a disposable tooth - they prey are then paralysed and die

56
Q

what do u-conotoxin GIIIA do

A

block skeletal NaV channels (little effect of neuronal NaV channels)

57
Q

what is batrachotoxin and how does it work

A

secreted by the skin of columbian poison frogs
it inhibits and shifts the activation voltage to more negative potentials so channels can stay open longer - then it enters the cell and acts internally

58
Q

what is pyrethrins and how do they work

A

a natural insecticide produced by plants (non-toxic on mammals)
rapid effect on insect Na channels - prolong activation and inhibit inactivation

59
Q

how do b-scorpion toxins work

A

bind to the outer side of the IIs4 voltage sensor - toxin binding alone has no effect but when the channel is activated by depolarization, the bound toxin enhances activation by negatively shifting the voltage dependance

60
Q

what do sea anemone and a-scorpion toxins do

A

uncouple activation from inactivation by binding to a receptor site at the extracellular end of the IVs4 segment and preventing its normal gating movement - as upward movement of IVS4 is thought to initiate fast inactivation, the channel remains in an activates “gated” state

61
Q

what do mutations of NaV 1.4 do

A

cause epidsodic and transient weakness or paralysis or relaxation defect
may affect fast inactivation gate causing channels to have slower inactivation kinetics and faster recovery from inactivation resulting in delayed muscle relaxation

62
Q

what do missense mutations of positive charged residues in the voltage sensor lead to

A

hypoexcitability or inexcitability and inability to depolarize muscle
sodium channels may also open after a delay and cause late depolarization and firing

63
Q

explain ventricular arrhythmia

A

conegnital long QT syndrome (10% of cases) and idiopathic ventricular fibrillation. observe a prolonged ventricular action potential duration. this is due to a persistent inward Na+ current causing abnormal repolarisation - various mutations of alpha subunit of NaV1.5 observed

64
Q

explain inherited epilepsy syndromes

A

many mutations (>100) found in alpha subunits (1.1 and 1.2) and some associated with beta1 subunit - variable outcomes - many induce persistent sodium currents or alter voltage dependence of activation/inactivation - causing enhanced excitability