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Ion channels and disease > L7- myotonia > Flashcards

L7- myotonia Flashcards

1
Q

what is myotonia + its symptoms?

A
  • a condition where there is hyper excitability of the skeletal muscles
  • due to delayed muscle relaxation
  • muscle stiffness
  • runs of action potentials (longer or more frequent)
  • myotonic seizures
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2
Q

what is the incidence of myotonia?

A

1 in 23000 to 1 in 50000

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3
Q

what mutations causes myotonia congenita?

A

CLCN1 (CLC1) gene mutation - loss of function

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4
Q

what mutations cause paramyotonia and K+ aggrevated myotonia?

A

SCN4A (Nav1.4) mutation - gain of function

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5
Q

why do mutations in CLCN1 (CLC1 channel) cause myotonia congenita?

A
  • CLC1 channel helps set resting potential
  • when Cl channels open - potential more negative - drives towards nernst potential for Cl (negative)
  • loss of function mutations in Cl channels mean the resting potential is not as negative as normal -so is closer to the threshold for an AP
  • more likely to fire an AP
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6
Q

what causes muscle contraction?

A
  • AP travels down T-tubule
  • voltage gated L-type Ca2+ channels open via rianodine receptors in T-tubule
  • increase in Ca2+ causes muscle contraction
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7
Q

what channel is important in AP firing?

A

Sodium channel - Nav1.4- causes depolarisation

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8
Q

what channels help keep resting potential away/more negative than threshold?

A

CLC1 channels and K+ channels

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9
Q

what happens in a muscle AP?

A

Nav1.4 channels open - causes more Na channels to open - if recahes threshold - depolarisation
- Nav1.4 channels close and Kv channels open - repolarsation

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10
Q

what are the two types of myotonia congenita?

A

thomsens and beckers

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11
Q

give the features of thomsens myotonia congenita

A
  • autosomal dominant
  • appears in infancy and adulthood
  • mild
  • warm up phenomenom - more they use muscles better it becomes - less stiff - encouraged to play musical instruments
  • muscle weakness (changes in muscle structure)- less cross bridges?
  • hypertrophy
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12
Q

give the features of beckers myotonia congenita

A
  • autosomal recessive
  • early onset
  • more severe then thomsens
  • warm up phenomenom
  • muscle weakness
  • more hypertrophy
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13
Q

what drug can be used to treat myotonia congenita?

A

mexiletene

  • dependent Nav channel inhibitor (if block Nav channels - less likely to reach threshold for AP)
  • don’t block all channels - given subthreshold dose - prevents excess contraction
  • acetazolomide - carbonic anhydrase inhibitor (change in PH can be beneficial to muscle function)
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14
Q

what mutations are identified in CLCN1?

A
  • are more recessive mutations (beckers?) identified than dominant mutations
  • mutaitons are randomly scattered throughout protein (no pattern)
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15
Q

what is the structure of a CLC1 protein/channel?

A

is a double barrel - with 2 pores

  • 4 subunits
  • 3 different gates - 1 gates for each pore and one big gate to cover whole channel
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16
Q

How does the current change when different gates of the CLC1 channel are open/closed?

A
  • all 3 gates open - max current
  • large gate closed - no current
  • one pore gate (one pore gate closed) and whole gate open - 1/2 max current
17
Q

what is the dominant mutant of CLC1?

A

I290M - DOMINANT NEGATIVE
- mutant subunit inhibits other 3 subunits - channel non - functional as all subunits have to work for the channel to be functional

18
Q

Why must effect of I290M be dominant negative?

A
  • when 50% of mutated protein was used in mix - not majorly different to WT Po voltage curve
  • mjust be dominant negative effect to have such a large effect

(there is slightly lower Cl- conductance)

19
Q

what do dominant mutations in CLC1 do ? (thomsens)

A
  • shift V1/2 more positive - so more positive potential is needed to open ClC1 channels - therefore there is more channels closed at rest - less negative resting potential - closer to AP threshold
  • less Cl- selective
  • dominant mutants effect WT subunits (DN effect)
20
Q

what does V1/2 move to in CLCN1 I290M mutation?

A
  • moves from -20 (WT) to +55 (mutant)
  • so potential required for 1/2 of the channel to be open is more positive
  • as resting potential is usually negative - less CLC1 channels are open
  • less Cl- current into the cell as lower Po
  • Resting membrane potential is more negative
  • closer to threshold for AP
  • AP fire more commonly/frequently
21
Q

what is the recessive mutant in CLCN1?

A

E291K (glutamic acid to lysine)

-beckers?

22
Q

why are carriers of the E291K mutations in CLCN1 asymptomatic for myotonia congenita and why is recessive condition more severe?

A
  • because 50% of normal/WT protein ca produce high enough currents of Cl- for normal function
  • but in full mutant there are no CLC1 currents - as there are no wt CLC1 channels - why recessive condition has more severe symtoms.
23
Q

What effect does E291K have on voltage dependence/ v1/2?

A

there is no shift in voltage dependence so therefore - no change in v 1/2
- are only looking at what WT channels are present as mutant channels are not even made - are completely non - functional

24
Q

give features of PARAmyotonia congenita

A
  • autosomal dominant
  • gain of function mutations in Nav1.4
  • appears neonatally-infancy
  • appears during exercise (worsens with activity)(NO warm up phenomenom)
  • cold sensitive
  • no hypertrophy
25
Q

give features of K+ aggrevated myotonia

A
  • myotonia occurs when too much potassium in body - e.g. eaten a banana
  • myotonia fluctuans - mild
  • myotonia permanens - severe
  • acetazolomide responsive - PH beneficial in muscle function
26
Q

where are the NAv1.4 mutations?

A
  • scattered throughout protein

- clustered in TMD 4

27
Q

How was muscle Na+ content determined in vivo of paramyotonia patients?

A
  • using MRI - magentic resonance imaging
  • 10 controls and 10 paramyotonia
  • leg Na+ content measured befroe and after cooling and exercise
  • Vm and IC Na+ determines from muscle biopsies
  • after cooling patients with paramyotonia had higher [Na+] intracellularly.
  • size of depolarisation in paramyotonia congentia patients was larger when cooled compared to controls (started with same parameters) - much closer to threshold as bigger depolarisaiton in cold
  • sodium channels open longer in PC patients
28
Q

what are features of Nav current?

A
  • fast activation to peak
  • fast inactivation
  • slow inactivation
29
Q

How was activation of Nav1.4 currents analysed in WT and mutant?

A
  • cell clamped at different potentials and looked at peak current - represents activation
  • G/Gmax plotted (relative conductance) - no differences in activation between WT and mutants investigated

(must be changes in inactivation)

30
Q

How was fast inacitvation (tail currents) of Nav1.4 channels investigated in mutants and WT?

A
  • one mutations (F1705I) has a slower/delay in inactivaiton
  • different potentials (pre-pulse) were measured and then all potentials changed to -10mv
  • If currents were measured the striaght away the differences in current will be due to differences in Po (this takes time to change) - but membrane potential changes immediatly
  • more positive the pre-pulse potential - greater degree of inactivation (lower the Po) (more channels close)
  • is a positive shift in voltage dependent inactivation in mutant - mutant channel needs +8mv more to get same dgeree of depolarisation - extended depol - channels stay open for longer to get same depol
31
Q

why is it thought that the cold has an effect on paramytonia congenita patients?

A

cold is thought to change the stucture and movements of the Nav1.4 channel even more - have bigger effect on inactivation

Ion channels and disease (11 decks)

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