channelopathies

Question 1

channelopathies

Answer 1

• Dysfunction of:
  • Voltage-gated ion channels (NA, K and Cl)
  • Ligand-gated ion channels (neurotrsnmitters)

Question 1

manifestations of NM channelopathies

Answer 1

• Can manifest in either of these:
  • Muscle fiber –> myotonia / paralysis / spontaneous contractions
  • Synapse –> failure of transmission / abnormal transmission
  • Motor nerve –> repetitive firing / spontaneous firing / conduction block

Question 2

ion channel functions

Answer 2

• To keep ion concentration regulated
• Resting potential –> K and Cl
• Action potential –> Na and K
• Synaptic transmission –> Ca and AcH
• Contraction –> Ca

Question 3

synaptic transmission at NMJ

Answer 3

1. Action potential reaches the presynaptic terminal of a motor neuron
2. Which activates voltage-gated calcium channels to allow calcium ions to enter the neuron.
3. Calcium ions bind to sensor proteins (synaptotagmins) on synaptic vesicles
4. Triggering vesicle fusion with the cell membrane and subsequent neurotransmitter release from the motor neuron into the synaptic cleft.
5. Motor neurons release acetylcholine (ACh), which binds to nicotinic acetylcholine receptors (nAChRs) on the cell membrane of the muscle fiber, also known as the sarcolemma.
6. AChRs let in Na+ which causes depolarization of the muscle fiber
7. Once the threshold of -55mV is reached the voltage gated Na-gates also open
8. This influx of sodium ions generates the EPP (depolarization), and triggers an action potential that travels along the sarcolemma and into the muscle fiber via the T-tubules (transverse tubules) by means of voltage-gated sodium channels.
9. The conduction of action potentials along the T-tubules stimulates the opening of voltage-gated Ca2+ channels which are mechanically coupled to Ca2+ release channels in the sarcoplasmic reticulum
10. The Ca2+ then diffuses out of the sarcoplasmic reticulum to the myofibrils so it can stimulate contraction.

Question 4

resting membrane potential

Answer 4

• Disequilibrium between ions inside and outside of cell
• The Goldman equation: concentration of K, Na and Cl inside and outside cell / the permeability of these = the membrane potential (at rest it is -65mV)
• Mainly due to low K outside and high inside neuron
  • If all channels were closed but the K-channels the resting potential would be -80mV
  • Not all K-gates are open so the K could go out but cant due to high Na+ presensce outside the neurons (+ charge repels the K until the Na+ gates open and Na goes into cell so K+ can go out)
• High Na outside neuron and low inside neuron
  • All sodium channels are normally closed otherwise the resting potential would be +55mV
• After resting membrane is restored the K/Na pump restores the balance to be able to fire again

Question 5

Na+ channels

Answer 5

• Opening in an all-or-none fashion
• Pore-forming α subunit + (modulating) β subunits
• Many different genes (e.g. skeletal muscle, motor nerve, sensory nerve after injury)
• Tetrodotoxin blocks Na+ channels –> decreases membrane excitability
• Leiurus toxin (scorpion) prevent closing of Na channels

Question 6

AChR

Answer 6

• 5 subunits (2a, 1b ,1y ,1d)
• Opens when binding Ach and closes when it goes away
• Endplate potential is caused by AcHR and full action potential is caused by opening of VGSCs

Question 7

NM toxins

Answer 7

• Curare blocks (nicotinic) AChR –> used to shortly paralyse people during surgery
• Alfa-bungarotoxin blocks AChR –> very toxic
• Alfa-Cobratoxin blocks AChR –> intermediate affinity still very toxic but can be used in research

Question 8

congenital myasthenic syndromes

Answer 8

• Mutations of proteins of the neuromuscular junction  causes weakness
• Gamma-unit of AChR commonly changes to epsilon-unit
• Includes mutations in rapsyn, agrin, Musk –> all contribute to AChR clustering
• Thus many different mutations can lead to the same pathogenic pathway of muscle weakness

Question 9

myasthenia gravis

Answer 9

• Antibodies have several effects:
  • Functional AChR inhibition: like curare or slow channel effect
  • Loss of AChR –> crosslinking of AchR by igG1 causes internalisation
  • Loss of AChR-associated proteins
  • Loss of postsynaptic membrane structure
  • Complement activation: Formation of membrane attack complex (Calcium influx or Depolarization by the membrane attack complex)
  • Antigenic modulation (AChR crosslinking)
  • There might also be ADCC that damages NMJ
• Can be against a few different proteins (agrin, LSk, musk, mainly AchR)

Question 10

neuromytonia and dendrotoxin

Answer 10

1. dendrotoxin or auto antibodies bind to VGKC
2. channel blocked
3. no repolarisation
4. hyperexcitability

Question 11

Potassium channel

Answer 11

• Pore-forming α1 subunit + (modulating) β subunits
• Many different genes for α1 subunit (more than 50 types!, many of which have a completely different architecture)
• Also non-voltage gated K channels occur. These are “leakage” channels important for the resting potential (e.g. TASK channels)
• Dendrotoxin –> blocks K channels –> hyperexcitability due to longer action potentials (less repolarisation)

Question 12

tetanus toxin

Answer 12

• The mechanism of TeNT action can be broken down and discussed in these different steps:
  • Transport:
  1. Specific binding in the periphery neurons by actions of the B-chains
  2. Endocytosis mediated by heavy chain
  3. Retrograde axonal transport to the CNS inhibitory interneurons (synaptic vesicle recycling)
  4. Transcytosis from the axon into the inhibitory interneurons
  • Action:
  1. Temperature- and pH-mediated translocation of the light chain into the cytosol
  2. Reduction of the disulfide bridge to thiols, severing the link between the light and heavy chain (by NADPH-thioredoxin reductase-thioredoxin)
  3. Cleavage of synaptobrevin (V-snare) at -Gln76-Phe- bond by the light chain
  4. Results in a lack of GABA  violent spastic paralysis
• No antidote for the toxin but there is vaccines against the bacteria that produce the toxin

Question 13

muscarinic AChR

Answer 13

• heart and brain not NMJ
• atropine: blocking (antagonist) the action of acetylcholine at muscarinic receptors, atropine also serves as a treatment for poisoning by muscarine like compounds
• Muscarine is a nonselective agonist of the muscarinic acetylcholine receptors (PNS)
• Physostigmine is a reversible cholinesterase inhibitor –> increase AcH presensce in synaptic cleft (antidote for atropine OD)