NaV Channels Flashcards
Gating and pore selectivity of the NaV channel
- pore is closed at -65mV
- pore is opened at -40mV
- partially hydrated Na+ ions fit through sodium channel selectivity filter, K+ ions do not
Describe the function of channels during the refractory period
channels are inactivated
How can channels be opened
- depolarisation
- open with little delay
- stay open for 1msec
- cannot be opened again by depolarisation
Function of the activation gate
- closes the channel at resting membrane potential
- Na+ enters the cell while activation gate is open
- reset to original position during repolarisation (K+ ions leaving cell)
Function of inactivation gate
- closes and stops Na+ entry
- delayed response to depolarisation
Explain what is meant by “activation is voltage dependent”
- the amount of Na+ current is dependent on the magnitude of the depolarisaiton
- as you get closer to equilibrium potential of sodium, drive for sodium to enter cell becomes smaller
The process of inactivation determines…
the number of Na+ channels available to open at any given membrane potential
Role of the Na+ channel auxillary subunits
- modulate channel gating allowing rapid activation and inactivation
- mutation in B1 associated with epileptic seizures
- immunoglobulin domains bind extracellular proteins and are important determinants of channel localisation in cells
How can changes in expression of TTX-resistant channels cause chronic inflammatory pain
- Na v1.8 and 1.9 are TTx-resistant isoforms found in peripheral NS
- found in sensory dorsal root ganglion neurons, including C-fibres (transmit pain)
- sustain repetitive firing of depolarised nerves
Role of Na v 1.7 in pain
- TTx sensitive
- expressed selectively in dorsal root ganglion nerves
- Nav1.7 mice have increased mechanical and thermal pain thresholds
- GoF mutation = cause of primary erythomelalgia (burning sensation and redness in response to mild thermal stimuli)
Mutations in Nav1.7 in humans
loss of Nav1.7 function, unable to feel pain
What happens to Na currents in grasshopper mouse in presence of venom
substantially diminished due to inactivation of Nav1.8 by venom
How local anesthetics work to block Na+ channels
- prevent action potential propagation
- cross the nerve sheath and cell membrane to reach site of action
- blocking is dependent on Na channel being open as it only blocks from the inside (use-dependent block)
- block is also voltage-dependent (enhanced by depolarisation)
- enhance Na+ inactivation process by stabilising it
Structure of local anaesthetics
aromatic group linked with amide or ester bond to basic side chain, mostly charged at physiological pH
What is Tetrodotoxin (TTX)
- naturally occurring
- virulent poison
- blocks nerve conduction
- causes death by respiratory paralysis
Where is TTX found
internal organs of Pacific puffer fish (ovaries, liver)
Mechanism of action of TTX
- blocks voltage-gated Na channels of neurons (nerves) and skeletal muscle
- blocks Na channels from outside of the channel (no effect from inside)
- binds to amino acid residues associated with outer mouth of channel
Effect of glutamate (-) to glutamine (neutral) mutation on P-loop
mM sensitivity is lost and TTX does not block
Effect of cysteine to tyrosine mutation in cardiac Na channel P-loop
affinity to TTX is increased
Where is the P-loop on the Na channel domain
between 5 and 6
What is saxitoxin (STX)
- has properties similar to TTX and blocks Na channels
Which toxins increase duration of Na channel opening
- batrachotoxin
- pyrethins
- b-scorpion toxins
- sea anemone and a-scorpion toxins
What are batrachotoxins
- secreteed by skin of Columbian poison frogs
- inhibits inactivation and shifts activation voltage to more negative potentials
- enters cell and acts internally
What are pyrethrins
- insecticides produced by plants
- non-toxic for mammals but rapid effect on insect Na channels
- inhibit inactivation
