Download Sodium channel poisons

Natural Sodium
Channel Poison
By: Abby(Qihang) Gan, Syed Hasan, Ji
Yoon Park, Ji Hee Choi
PHM142 Fall 2016
Instructor: Dr. Jeffrey Henderson
November 23, 2016
Sodium Channels
- Integral membrane proteins that form ion channels
- conducts sodium ions through plasma membrane
- Highly selective
- Classification:
- voltage-gated sodium channels
- ligand-gated sodium channels
Voltage-gated Sodium Channels
- Responsible for action potential initiation and propagationin
excitable cells
- Unclear physiological role in unexcitablecells
Ligand-gated Sodium Channels
● Found in neuromuscular
junctions as nicotinic
receptors
○ Ligands =acetylcholine
● Response: create change
in membrane potential first
Natural Poisons
- Types:
-
blockers
peptides
non-peptides
lipoproteins
gating-modifiers, etc.
- Examples:
- Tetrodotoxin (TTX)
- Saxitoxin (STX)
- Batrachotoxin (BTX)
Tetrodotoxin (TTX)
● Extremely potent neurotoxin (than cyanide)
● Found in various animals: pufferfish, blue-ringed octopus, crabs, marine
snails, frogs, newts, etc
○ Pufferfish: important since considered delicacy in Japan (called
“Fugu”);
■ Preparation by specially licensed chefs
■ TTX concentrated in organs (esp. liver & ovaries)
● Produced by bacteria living in a mutualistic symbiosis with animals
○ ie. Vibrio and Pseudomonas
TTX - Mechanism of action
● Very high affinity for voltage-gated sodium channels
● Binds and blocks the ion channel
○ Hypothesis: binding of guanidinium group (TTX) with carboxylate
groups (residues in channel)
● No sodium influx = no depolarization = no action potentials
○ Lead to muscle paralysis
● Pufferfish: immune to TTX
○ Point mutation in sodium channel
TTX - Symptoms of poisoning
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Symptoms show up in 10 min ~ 6 hours
Initial symptoms:
○ paraesthesia (tingling, pins & needles)
of lips & tongue
○ numbness of face and fingers
○ headache
○ excessive sweating
○ salivation
○ nausea
○ emesis
○ diarrhea
○ GI pain
Death: in 20 minutes ~ 24 hours
●
Later symptoms:
○ hypotension
○ speech difficulties
○ muscular weakness
○ difficulty moving
○ paralysis
○ difficulty breathing
○ respiratory arrest
○ death
TTX - Treatment
●
●
●
No antidote
Treatment is primarily supportive:
○ Monitor vitals
○ Secure airway: endotracheal intubation if respiratory arrest
○ Establish IV line: if medication needed
○ Administer activated charcoal: bind toxin and possibly utilize gastric
lavage
Those who survive the first 24 hours generally recover
○ Recovery can take days
Saxitoxin (STX)
- water soluble, non-peptide neurotoxin
- paralytic shellfish toxins
- dinoflagellates and cyanobacteria - shellfish - humans
saxitoxin
Saxidomus gigantea
Saxitoxin - mechanism of action
- voltage gated sodium
channels
- direct blockage of ion
pore
- also calcium and
potassium channels
Saxitoxin - symptoms and treatment
-
tingling/burning lips, mouth, and throat; facial numbness
perspiration, diarrhea, vomiting
muscular weakness, loss of motor coordination, paralysis
respiratory arrest, cardiovascular shock, death
no clinically approved treatment
Batrachotoxin (BTX)
● One of most potent natural toxin
● Neurotoxic and cardiotoxic steroidal alkaloid
● Found in certain species of frogs, beetles, birds:
○
○
○
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Poison dart frog
Melyrid beetles
Pitohui
Blue-capped ifrit
Little shrikethrush
● Colourless, milky secretions from glands on back and behind ears
○
released when agitated, threatened, or in pain
Batrachotoxin - mechanism of action
● Effects in PNS and in heart
● Irreversible binding to
voltage-gated sodium
channels
● Keep channel open → by
lowering threshold potential
● Paralysis
Batrachotoxin - symptoms and treatment
● Severe effect in heart:
○
○
○
○
○
impairment in cardiac function
arrhythmias
extrasystoles
ventricular fibrillation
heart arrest
● No effective permanent antidote
○
hypothesis: bind only in open conformation
● Temporary treatment: TTX or STX
○
○
receptor antagonist
competitive antagonist
Summary
●
Sodium channels: highly selective, ion channel with two classes→
voltage-gated and ligand-gated
○
●
important in action potentialinitiation
Natural Poisons: no permanent antidote; effects toneural, muscular,
respiratory and cardiovascular system
○
○
○
TTX: found in pufferfish
■ Direct blocker of sodium channels withhigh affinity
■ No sodium influx = no depolarization = no action potentials leading to paralysis
STX: found in paralyticshellfish
■ Direct blocker of sodiumchannels
■ also affect calcium and potassiumchannels
BTX: found in poison dartfrogs
■ irreversibly bind causing permanent opening ofchannel
■ leading to paralysis of muscles and effectsin heart
References
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http://www.chm.bris.ac.uk/motm/ttx/ttx.htm
http://www.life.umd.edu/grad/mlfsc/zctsim/ionchannel.html
http://emedicine.medscape.com/article/818763-overview
http://www.cdc.gov/niosh/ershdb/emergencyresponsecard_29750019.html
http://emedicine.medscape.com/article/818763-treatment#showall
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663416/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877881/
http://www.jyi.org/wp-content/uploads/JYI-Volume-23-Issue-2-Faber-Samantha_Saxitoxin-and-the-induction-of-paralytic-she
llfish-poisoning4.pdf
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3705384/
http://www.dereilanatureinn.ca/lagoon/marine-guide/b-5.htm
http://www.wou.edu/las/physci/ch350/Projects_2006/Grimes/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC430544/
http://www.chm.bris.ac.uk/motm/batrachotoxin/batrah.htm