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Physiology and Pharmacology of Cells > L14 - Neuronal and Muscle Toxins > Flashcards

L14 - Neuronal and Muscle Toxins Flashcards

1
Q

What toxins is the neuronal Na channel affected by?

A

Tetrodotoxin

Saxitoxin

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2
Q

What toxins is the muscle Na channel affected by?

A

Tetrodotoxin
Saxitoxin
Conotoxin

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3
Q

What toxins is the Ca channel affected by?

A

Conotoxin

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4
Q

What toxins is the Kv K channel affected by?

A

Dendrotoxin

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5
Q

What toxins is the AchR channel affected by?

A

Tubocurarine

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6
Q

What toxins is Ach release affected by?

A

Tetanus toxin

Botulinum toxin

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7
Q

What is tetrodotoxin?

A

Guanidinium neurotoxin
100 times more lethal than spider toxins
10,000 times more lethal than cyanide
Only nM levels required

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8
Q

What does tetrodotoxin inhibit?

A

Voltage gated Na channels

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9
Q

What is the source of tetrodotoxin?

A

Produced by marine bacteria found in invertebrates, amphibians, fish
- Puffer fish, blue ring octopus

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10
Q

What are the symptoms of ingestion of tetrodotoxin?

A 
Numbness of lips and tongue
Facial paraesthesia - abnormal sensation 
Headache
Nausea
Dizziness
Diarrhoea
Vomiting
Increasing paralysis and respiratory paralysis - death
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11
Q

What is the rate of onset of symptoms following ingestion of tetrodotoxin?

A

20 mins to 8 hours

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12
Q

What are the symptoms of a bite containing tetrodotoxin?

A

Same as ingestions but without facial effects

Faster death

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13
Q

What are the treatment for tetrodotoxin poisoning?

A

Mechanical ventilation

No anti-venom - tetrodotoxin binds too strongly to site of action

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14
Q

In tetrodotoxin what does the inhibition of voltage gated Na channels lead to?

A

Failure of neurotransmission – reduction in Ach release at NMJ

  • Loss of sensation and then muscle paralysis
    • Because sensory neurons meet the toxin first
  • Respiratory paralysis and death
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15
Q

What are some examples of tetrodotoxin sensitive channels?

A 
Nav 1.1 SCN1A – CNS and heart
Nav 1.2 SCN2A - CNS
Nav 1.3 SCN3A – CNS and heart
Nav 1.4 SCN4A - skeletal
Nav 1.6 SCN8A - CNS and PNS
Nav 1.7 SCN9A - PNS
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16
Q

What are some examples of tetrodotoxin insensitive channels?

A

Nav 1.5 SCN5A - heart
Nav 1.8 SCN10A - sensory
Nav 1.9 SCN11A - PNS

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17
Q

Which channel highlighted the variable sensitivity to tetrodotoxin?

A

Rat Nav type II

18
Q

Rat Nav type II tetrodotoxin sensitivity?

A

Wildtype rat channel - tetrodotoxin sensitive
Mutations in E387Q in pore region of rat channel
- Glutamate –> glutamine
- Tetrodotoxin insensitive
- Shows that tetrodotoxin sensitivity is based on one amino acid substitution in pore region

19
Q

Heart Nav 374 tetrodotoxin sensitivity?

A

Heart Nav 374 – cysteine - tetrodotoxin insensitive

Change heart 374 to tyrosine - tetrodotoxin sensitive

20
Q

What animals shows variable sensitivity to tetrodotoxin?

A

Garter snakes
- Difference geographical areas
- Different tetrodotoxin sensitivity
- Different Nav sequence IV domain
Both eat salamanders which can contain tetrodotoxin
- Only 1 snake population affected
- The snake population that survived was able to reproduce and pass on this gene

21
Q

Where are dendrotoxins found?

A

Snake neurotoxins found in Mamba family

Only nM levels required

22
Q

What do dendrotoxins inhibit?

A

Inhibit Kv channels

  • Different types block different Kv subtypes
  • Inhibition of repolarisation
23
Q

What are the symptoms of infection with dendrotoxins?

A

Early weakness and numbness in the bitten extremity
Systemic responses 30 minutes to 1 hour after bite
Ptosis - drooping eyelids
Ophthalmoplegia – paralysis of eye muscles
Disphagia - difficulty swallowing
Paresis - mild paralysis
Respiratory failure - death

24
Q

In dendrotoxin what does the inhibition of voltage gated K channels lead to?

A

Delays repolarisation of NMJ
Excess release of Ach from pre-synaptic membrane leading to Ach depletion
Failure of subsequent neurotransmission
Problems with muscle control - respiratory paralysis and death

25
Q

Where is conotoxin found?

A

Found in cone snails

26
Q

What are the different types of conotoxin?

A

Over 8000 different conotoxins
- 19 major gene families
Multiple and diverse targets - many channel types
Varying lethality

27
Q

What are conotoxins being investigated for/

A

Parkinson’s, MS, lung cancer and chronic pain

28
Q

What are the symptoms of infection with conotoxin?

A 
Burning pain
Swelling at site of toxin injection
Numbness 
Cardiac and respiratory distress 
Muscle weakness
Loss of coordination
Ptosis
Headache
Nausea
Stomach cramps
29
Q

What are the symptoms of infection with conotoxin in severe cases?

A

Lips became stiff
Blurred vision
Paralysis
Coma

30
Q

What are the two conotoxin pain targets?

A

Found in nociceptive nerve endings
Ca 2.2
- Found in pre-synaptic membrane and sensory neurones
- Mediates the release of neurotransmitter and therefore propagate pain
- Inhibited by Eu1.6
Na 1.8

31
Q

What does Eu1.6 inhibit in HEK cells?

A

Cav2.2
In control as cell depolarised the Ca currents increase
In Eu1.6 the Ca currents are much smaller –> inhibits Cav2.2 –> fewer vesicles fuse –> less neurotransmitter

32
Q

What does Eu1.6 inhibit in rate DRG cells?

A

Cav2.2
Looking at Cav2.2 in a cell where it is normally expressed
Used barium – do not get the negative feedback seen with calcium which inhibits the channel
In Eu1.6 the currents are much smaller than in control - blocks 1/3 of the channels - 30% inhibition

33
Q

What experiment was used to see if Eu1.6 suppresses pain?

A

Rat partial nerve ligation

  • Rat anaesthetised and sciatic nerve exposed
  • Pain model – 1/3rd of the sciatic nerve tied off
  • Application of pressure to hind paw until withdrawal
34
Q

What were the 3 groups tested during the rat partial nerve ligation?

A

No pain relief – saline
- Feel pain with a low amount of pressure
- Positive control - morphine and gabapentin
- After injection able to withstand higher pressure
Eu1.6
- After injection able to withstand higher pressure

35
Q

What is the overall effect of Eu1.6?

A

Inhibition of voltage gated Ca2+ channels
Reduction in release of neurotransmitter at synaptic cleft
Reduction in pain signalling

36
Q

What are two examples of tarantula toxins?

A

µ-TRTX-Tp1a and GpTx-1

37
Q

What do µ-TRTX-Tp1a and GpTx-1 do?

A

Inhibit Na+ currents through Nav1.7 –> can’t generate action potentials in sensory nerves
- Potential to block pain signals
Open probability is less in the presence of the toxin

38
Q

What experiment was undertaken to see if GpTx-1 was an analgesic in mice?

A

Pain model - 40 µl of OD1 injected into hindpaw

GpTx-1 then blocks the Na channels that OD1 activated

39
Q

What is OD1?

A

Scorpion toxin

40
Q

What does OD1 causer?

A

40 µl of OD1 injected into hindpaw
Activates Nav1.7/1.6
Activates action potential firing in A and C fibres –>channels stay open for longer
- Pain felt in paw – shown by lifting, shaking and licking

Physiology and Pharmacology of Cells (13 decks)

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