Non canonical functions of voltage-gated sodium chanenels Flashcards
Timing of life events
DNA replication and cell division
1 day
Timing of life events
Gene transcription / protein syntesis
1 hour
Timing of life events
Hormone regulation
1 min
Timing of life events
Enzymatic activity
0.1 - 1 sec
Timing of life events
Electrical signals
(vision, hearing, nerve conduction, muscle conduction)
1 millisec
Moving ions make electronical signals
Ascendent rapid phase : Na+ enters in the celle -> inside positive
Descending phase : K+ leaves the cell -> returns to negative resting potential
Mesurement of electrical signals
we use patch clamp technique
Conformational states of sodium channels
Close state
Activates/open state
Inactivated state : the ions cannot pass because of a blocking protein
to be open again we have to wait = “phase de latence”
Perfect model to study sodium channels
Squid
Toxins to paralyze prey
Toxins target sodium channels to paralyze prey :
opiates can supress the possibility to inactivate the channels by blocking the blocking protein
Toxins in different animals like spiders, scorpions and snakes
To paralysis a prey
Alpha scorpion toxin slows down the mecanism of inactivation, the fibres and the nerves are blocked => paralysis
TTX
Specific way of killing and cooking it otherwise he will intoxicate you
Toxin called Tetrodotoxin (TTX)
produced by a marine bacterium
It blocks activity of Na+ channels
Local anesthesics
preventing the pain by blocking the activity of Na+ channels
Other blocking drugs are used in treatments of epilepsy, cardiac arythmia ans chronic pain.
Discovery of sodium channel protein molecule
Work of Pr William CATTERALL
Difficult because more than 20 000 types of proteins molecule in the brain
Family of sodium channels
9 members classified depending on the
- TTX-sensibility
- TTX-resistance
Caracterised voltage dependent channels
conductance, ion selectivity, pharmacology, voltage-sensitivity
Begining of the story cancer/Na+ channels
If there is a membrane you can patch it !
Cancer cells
When you block the activity of the Na+ channells by using TTX, you decrease the number of cells that are invading
Inhibition des protéines Nav 1.5 diinue l’invasion des cellules cancéreuses
Breast cancer over expression of ARN transcript of the proteins of Nav 1.5
associated with a poor prognostic
Same for colon cancer
Cervical cancer
Nav 1.6
use specific toxin (TTX) -> inhibit the invasive capacity by about 20%
pH
pH increases after blocking of the channels
Ranolazine breast cancer
used to treat cardiomyopathy because it blocks Nav1.5
could be very useful to fight metastasis in organisms
Phenotoin
inhibits breast tumor growth and metastasis
Ronolazine prostate cancer
Anti-metastatic effect of Ronolazine using an in vivo rat model of prostate cancer
- reduces tumor volume
- reduces the number of metastasis
Conclusion
The targeting of these txo preteins (Nav and NHE1) is an opportunity to fight and decrease metastasis.
