BB Lecture 9: NMJ Normal and Pathological

Question 1

Safety Factor

Answer 1

i. under normal physiologic conditions, the endplate potential generated by the release of 20% of the immediate store vesicles always generate an end plate potential voltage well above ~50mV
ii. difference between the endplate potential and -50mV is known as the safety factor for NMJ transmission
iii. there is a decrease of EPP, but the decrease never falls below -50mV

Question 2

Synaptobrevin

Answer 2

vesicle membrane protein; essential for vesicle release; binds to SNAP-25 and syntaxin on presynaptic membrane

Question 3

SNAP-25 and Syntaxin

Answer 3

proteins on cytoplasmic side of presynaptic membrane; binds to Synaptobrevin; allows vesicle release

Question 4

Lambert-Eaton Disease aka Lambert-Eaton Myasthenia Gravis (LEMS)

Answer 4

• can be caused by squamous cell lung cancer

- antibodies are formed against Ca channel

Question 5

primary, secondary and tertiary vesicles

Answer 5

1. primary (1000) vesicles: ready for immediate release
2. mobilization (secondary) vesicles: 10,000; can refill primary store in a few seconds
3. reserve (tertiary) store (100,000): reserve stores

Question 6

acetylcholinesterase

Answer 6

breaks ACh into acetate and choline

Question 7

Nicotinic acetylcholine receptors (adult and fetal)

Answer 7

fetal and adult different; need 2 ACh to bind to it in order to activate it; you can different types of antibodies depending on A or F types of receptors

Question 8

MUSK (muscle specific tyrosine kinase) protein

Answer 8

part of ACh receptor complex; antibodies to this will fuck with the receptors

Question 9

Botulism

Answer 9

clostridium botulinum

MOA: uses proteinases to digest synaptobrevin or SNAP25/syntaxin

Question 10

Organophosphorus gases (sarin)

Answer 10

-react with AChE irreversibly
-activates nicotinic receptor repetitively
Significance: notable for causing spasticity at first but THEN paralysis because Na channels get inactivated (by lowering of threshold to -45mV)

Question 11

Autoimmune Myasthenia Gravis

Answer 11

MOA: antibodies directed at AChE receptor and MuSK

Question 12

Succinylcholine

Answer 12

post-synaptic; succinyl choline and -Paralytic used in anesthesia

• keeps postsynaptic sodium channel activated
• LIKE ORGANOPHOSPHORUS GASES, contraction caused at first, but ultimately paralysis takes place when sodium channels enter inactive state

Question 13

Falling below safety factor

Answer 13

Mechanism of NMJ disease

Question 14

Complete inhibition of AChE paradoxically

Answer 14

Leads to paralysis because of new threshold (-45mV) formed required for SODIUM channel opening on POSTsynaptic terminal

Question 15

Symptoms of Lambert Eaton

Answer 15

• improves during brief exercise
• repetitive depol causes increased presynaptic [Ca]
• proximal limb weakness (worse in legs

Question 16

Symptoms of Botulism

Answer 16

Weakness in face that then descends to limbs and respiratory muscles; common in infants; treated with botulinum immunoglobulin (BIG)

Question 17

Tetanus

Answer 17

• clostridium of tetanus
  
  • acts on synaptobrevin, SNAP-25, syntaxin
  • prevents vesicle fusion, but prevents inhibitory signals at the UMN/LMN level
  • because it prevents inhibitory signals from UMN, then you get spasticity

Question 18

Physostigmine, Neostigmine, Pyridostimine

Answer 18

• PARTIAL AChE inhibition
• compounds that competitively binds AChE
• used to treat NMJ disease (specifically post-synaptic dysfunction

Question 19

Symptoms of Autoimmune Myasthenia Gravis

Answer 19

• gets worse with repeated use
• ptosis, double vision, difficulty chewing/swallowing, proximal limb weakness
• does NOT get better with calcium influx but does get better with AChE inhibition

Question 20

Partial inhibition of AChE

Answer 20

used therapeutically to treat NMJ impairment