Neurotoxins

14 important questions on Neurotoxins

What is a neurotoxin?

Potent toxin which acts selectively on the nervous system; lethal at very low concentrations (ng-µg)

What kind of neurotoxins do plant/fungi and bacteria/animals produce?

Plant/fungi = small molecules
Bacteria/animals = peptides or proteins

--> can be synthesized in the lab for commercial use

Why do we study neurotoxins?

For healthcare - therapy, addiction, local anesthetics, muscle relaxants and pain killers
For neurosciences - staining, functional analyses of ion channels and blocking functions
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What is the main role of the Na+ channel and what is the structure of this channel?

Eliciting an AP by depolarizing the cell membrane (Na+ influx)

Made up of 4 transmembrane subunits, which are encoded by different genes giving riseto different types of channels

What do Na+ channel toxins do and to which site of the channel do they bind?

- Pore blockers (site 1)
- Gating modifier (site 2 or 5)
    • Inactivation inhibitor (site 3)
    • Activation enhancer (site 4)

What is the function of pore blockers (Na+ toxins)?

Less activation of the channel -> blocking of AP
These toxins bind to site 1 of the channel

What is the function of gating modifier Na+ toxins?

Persistent depolarization
Inactivation inhibitor = decreases inactivation -> more APs
Activation enhancer = shifts activation potential to a more negative value, so whole IV curve switches to the left -> less depolarization leads to opening of the channels -> APs

What is the effect of botulinum neurotoxin?

Paralyses of several skeletal muscles
CNS is not affacted as the neurotoxin cannot cross the blood-brain barrier

How are people infected with botulinum neurotoxin?

Food-borne, inhalation, iatrogenic (too much Botox) and wounds
Infant botulism = caused by honey containing spores of the bacterium

What is the target of the neurotoxin botulinum?

- Polysialyated gangliosides present at nerve terminals, in particular the cholinergic receptors (cholinergic synapses) at the NMJ

- Vesicular membrane proteins: SV2 and synaptotagmin

What happens when neurotoxin botulinum binds to its targets?

Enters the axon, where the light chain can cleave proteins involved in neurotransmitter release (SNARE proteins) -> blocking of synaptic transmission

How can sodium channel toxins used as potential drugs?

As potential drugs they can modify the characteristics. When sodium channels are disfunctional, you can have too much or too few pain. Pain is transmitted by neurons which have sensing parts in the skin, and sodium channels there are responsible for eliciting an action potential that causes pain. There are multiple mutations in humans that cause problems in these receptors. Neurotoxins can be a potential treatment for this. For example, over active sodium channels can be blocked to help in pain.

How many domains has the botulinum neurotoxin?

3, light chain, translocation domain and binding domain

How is neurotoxin botulinum used as a therapeutical compound?

They have to be used in very very extreme dilutions because they aree so potent, and they have to be used locally. It is used to treat spontaneous muscle twitchings, or dystonia in the cervical areas, also hyperhidrosis (extreme sweating), overactiity of the bladder, some forms of migrane, cosmetic application (botox). Can be reversed, but there aree already some researches that say the effects can be longer then we thought.

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