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Physiology and Pharmacology of Cells > L10 - CNS Channelopathies > Flashcards

L10 - CNS Channelopathies Flashcards

1
Q

What is episodic ataxia?

A

Irregular, uncontrolled muscle contractions
< 1 in 100,000
At least 6 types - type I and II seen in multiple families

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2
Q

What is type 1 episodic ataxia?

A

Autosomal dominant
Onset of symptoms - 10-20 years
Ataxia, dizziness
Attack length - brief

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3
Q

Which channel mutation is type 1 episodic ataxia linked to?

A

Linked to mutations in KCNA1 (KV)

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4
Q

What is type 2 episodic ataxia?

A

Autosomal dominant
Onset of symptoms - childhood to teens
Ataxia, vertigo, nausea, headache
Attack length - 30 mins to 24 hours

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5
Q

Which channel mutation is type 2 episodic ataxia linked to?

A

Linked to mutations in CACNA1A (CaV)

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6
Q

What is the trigger for type 1 episodic ataxia?

A

Physical or emotional stress
Impacts on vestibular system
Abrupt changes in position

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7
Q

What are the symptoms of type 1 episodic ataxia?

A

Ataxia, dizziness, visual blurring

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8
Q

What are the causes of type 1 episodic ataxia?

A

Caused by loss of function mutations in KCNA1 (KV)
- Only need 1 subunit to stop working to produce disease
- Increased excitability due to low K channel function
Expressed in neurons in the cerebellum and neuromuscular junction

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9
Q

What is the treatment for type 1 episodic ataxia?

A

Acetazolamide – carbonic anhydrase inhibitor
Phenytoin – Na+ channel blocker
Carbamazepine - Na+ channel blocker

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10
Q

What is the trigger for type 2 episodic ataxia?

A

Physical or emotional stress

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11
Q

What are the symptoms of type 2 episodic ataxia?

A 
Ataxia
Trunk instability
Nystagmus
Vertigo
Nausea
Vomiting
Headache
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12
Q

What are the causes of type 2 episodic ataxia?

A

Caused by point mutations in CACNA1A (CaV)
- 1A Ca2+ channel – part of the P/Q type Ca2+ channels
- Most truncation mutations - severe
- Some non-truncating – less severe
Expressed in neurons in the cerebellum – degenerative neuron disease
Loss of function mutations means a reduction Ca2+ influx
- Problems neurotransmitter release
- Problems control skeletal muscle

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13
Q

What is the treatment for type 2 episodic ataxia?

A

Acetazolomide – carbonic anhydrase inhibitor

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14
Q

What are the 3 allelic disorders caused by CACNA1A?

A

Mis-sense mutations – familial hemiplegic migraine
Repeat expansion C terminus - spinocerebellar ataxia type 6
Shows that mutation position and type determines the phenotype

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15
Q

Where are CACNA1A channels found?

A

Purkinje cells
Granule cells
Cell bodies central neurones
Ca channel role is - exocytotic neurotransmitter release triggered by increased Ca concentrations

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16
Q

What is the CACNA1A knockout mice phenotype?

A

Up to 10 days after birth - normal
10 days after birth - balance problems and ataxia begin
Falls with twisting movements
Death 3-4 weeks after birth

17
Q

What is the difference between WT or G293R mice?

A

Barium current – goes through Ca channel pore but unlike Ca does not cause the channel to close giving more stable recordings
Small barium currents recorded in mutant – loss of function of Ca channel
As open probability increases as do the currents
In WT – maximum current recorded at 0mV
In mutant – maximum current recorded at 3mV
- Needs a bigger depolarisation to get the same open probability as in the wild type
- Smaller current and they take longer to open

18
Q

What is epilepsy caused by?

A

Seizures caused by episodic neuronal discharges

Caused by infection, tumours, brain trauma, inherited

19
Q

What are the different epilepsy phenotypes?

A

Areas of brain affected determine symptoms
Partial – only small parts of brain affected
Generalised – larger areas of brain affected
Simple – no loss of consciousness
Complex – loss of consciousness

20
Q

What are the roles of ion channels in inherited epilepsy?

A

Benign familial neonatal seizures
Absence epilepsy and episodic ataxia
Focal epilepsy and episodic ataxia

21
Q

What are the roles of ion channels in acquired epilepsy?

A

Changes in ion channels in response to damage

Autoimmune diseases

22
Q

What are the roles of inhibitory and excitatory neurones role?

A

Inhibitory neurones release neurotransmitter which supress activity in the excitatory neurones
Seizure caused by
- Too much activity in excitatory neuron
- Too little activity in inhibitory neuron

23
Q

Neuronal ion channels role

A

Nav - depolarisation
Kv - repolarisation
Cav - neurotransmitter release synapse
AchR – post synaptic membrane activation
GABAA – post synaptic membrane inhibition
- Chloride channel hyperpolarising membrane
HCN – hyperpolarisation-activated cyclic nucleotide gated channel - depolarisation

24
Q

Where is NaV1.1 found?

A

In inhibitory interneurons

25
Q

What is the structure of NaV1.1?

A

24 transmembrane spanning domains in four blocks of 6

4th transmembrane spanning domain of each block is a sensor

26
Q

What is the wild type function in a NaV1.1 interneuron?

A

Action potential firing normal leading to release of inhibitory GABA
Suppression of activity in surrounding excitatory neurons

27
Q

What happens in a +/- Nav1.1 interneuron?

A

Mimic Epilepsy – loss of suppression of excitatory neurons

Action potential firing reduced

28
Q

What are the main two mutations found in NaV1.1?

A

Loss of function
- Too much activity in excitation neurones
- Too little activity in inhibitory neurones
Gain of function
- No clear reason why these mutations lead to epilepsy

29
Q

Different NaV1.1 mutations have different severity

A 
Mild – missense 
- Febrile seizures
Moderate – missense 
- Febrile and generalised seizures 
Severe – missense 
- Febrile and generalised seizures
Truncation – loss of function
- Febrile, generalised and myoclonic seizures 
- Ataxia 
- Cognitive impairment
30
Q

NaV1.1 summary

A

Location - inhibitory interneurons
Effect - loss and gain
Impact on excitatory output - increased due to loss of inhibition

31
Q

GABAAR summary

A

Location - post synaptic membrane inhibitory neurones
Effect - loss
Impact on excitatory output - increased due to loss of inhibition

32
Q

AchR summary

A

Location - post synaptic membrane excitatory neurones downstream of other excitatory neurones
Effect - gain
Impact on excitatory output - increased due to excessive AchR activity

33
Q

NaV1.2 summary

A

Location - excitatory axons
Effect - gain
Impact on excitatory output - increased due to excessive Nav1.2 activity

34
Q

HCN summary

A

Location - excitatory dendrites
Effect - loss
Impact on excitatory output - increased due to loss of firing control

35
Q

KV7.2 summary

A

Location - excitatory axons
Effect - loss
Impact on excitatory output - increased due to loss of firing control

36
Q

What are the benefits of pain?

A

Protective
Avoidance – to stop damage or warn of damage
- E.g. heat

37
Q

What are the two types of rare inherited pain disorders?

A 
Nav1.7 peripheral sensory neurones
Loss of pain
- Loss of function Nav1.7 – can’t fire action potentials 
- Symptoms - injuries and early death
Enhancement of pain 
- Gain of function Nav1.7
- Symptoms – redness, heat and burning pain 
- E.g. Erythromelalgia

Physiology and Pharmacology of Cells (13 decks)

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