disease of the week- NMJ diseases

Question 1

diseases of NMJ:
what are the 2 toxins that inhibit transmitter release, lowering transmitter concentration in the synaptic cleft

Answer 1

tetanus & botulinum

Question 2

what kind of proteins are tetanus and botunilum? and what is their mechanism for lowing transmitter concentration in synaptic cleft?

Answer 2

protease enzymes

selectively attack and break down proteins (synaptobrvein, SNAP-25, syntaxin) required for docking of synaptic vesicles with the presynaptic membrane

Question 3

tetanus is an infection caused by what bacterium?
where is it found

Answer 3

Clorstridium tetani
spores of tetanus bacteria found everywhere in the environment- soil, dust, manure

Question 4

describe structure of tetanus toxin protein

Answer 4

MW = 150 kDa, translated from TetX gene which is then cleaved into 2 parts:

a 100kDa heavy/B-chain and a 50 kDa light/A-chain
chains connected by disulfide bond
- B-chain binds to disialogangliosides on neuronal membrane and has a translocation domain which helps movement of protein across membrane into neuron
- A-chain (a zinc endopeptidase) attacks the vesicle-associated membrane protein

Question 5

what is the action of the A-chain of tetanus toxin protein

Answer 5

stops the affected neurons from releasing the inhibitory neurotransmitters GABA and glycine by degrading the protein synaptobrevin

• consequence = dangerous overactivity in muscles from the smallest stimulus (tetanic spasm)

Question 6

typically, skeletal muscles are controlled by multiple nerves- some are excitatory and cause contraction, called ___ , others are inhibitory and prevent contraction, called ___

Answer 6

agonist
antagonist

Question 7

tetanus toxin called ___ paralysis, which stops ___

Answer 7

spastic
uncontrollable muscle contraction

Question 8

botulinum toxin called ___ paralysis, which stops ___

Answer 8

flaccid
muscle contraction

Question 9

describe food-borne botulism and ingestion that causes botulism

Answer 9

• food-borne botulism usually results from ingestion of food that has become contaminated with spores of the bacterium Clostridium botulinum in an anaerobic environment, allowing spores to grow –> the growing vegetative bacteria produce toxin
• its the ingestion of preformed toxin that causes botulism, not the ingestion of the spores or vegetative bacteria

Question 10

at what temp is Clostridium botulinum growth retarded?
what else is it susceptible to?

Answer 10

3 celcius (38 F)

susceptible to high salt and low pH levels

the toxin is rapidly destroyed by heat, like in cooking

Question 11

what toxin has been recognized and feared as a potential bioterror weapon?

Answer 11

botulinum toxin

Question 12

how many structures are there of botulinum toxin? how many toxin types?

Answer 12

over 70 structures

there are 7 serologically distinct toxin types, designated A-G

• 6 of the 7 toxin types have subtypes with 5 subtypes of BoNT A having been described

Question 13

describe structure of botulinum toxin

Answer 13

a two chain polypeptide with a 100 kDa heavy chain and a 50 kDa light chain connected by disulfide bond

• the light chain is a protease enzyme that attacks one of the fusion proteins (synaptobrevin, syntaxin, SNAP-25) at a NMJ, preventing vesicles from anchoring to membrane to release Ach (by doing this, the toxin interferes with nerve impulses and causes flaccid paralysis of muscles in botulism

Question 14

what is the most acutely toxic substance known

Answer 14

botulinum toxin

Question 15

what are the 2 other compounds involved in NMJ diseases and what is their mechanism

Answer 15

organophosphates and carbamate based insecticides

• toxic b/c they act at the site of the NMJ and at any synapse that uses Ach as a neurotransmitter (their mechanism of action is to inhibit Ach-esterase

Question 16

how do organophosphates inhibit Ach esterase?

Answer 16

by phosphorylating a serine residue at the active site of the enzyme, “aging” occurs when a side group is removed and replaced by OH from water –> results in formation of a strong covalent bond with the hydroxyl group of serine (once this happens, very hard to reverse the inhibition)

Question 17

what can prevent “aging” in organophosphates?

Answer 17

rapid treatment with pralidoxime prevents aging y replacing the side group and preventing the rxn with water

–> Ach esterase activity is restored

Question 18

what receptors can organophosphates inhibit?

Answer 18

both nicotinic and muscarinic

Question 19

occurrence of organophosphates

Answer 19

~ 1 million cases worldwide per year, with about 200,000 deaths

• most common in rural(farming) areas and developing countries

exposure: skin, inhaling, drinking, vapors

• more common as method of suicide