What part of the channel is important for gating the activation ?
4th transmembrane domain. Moves inwardly when there is a large depolarisation current (through attraction) causing the activation of the channel.
What happens during the absolute refractory period?
Channels are inactivated. At this stage, no further AP will be generated.
What does the sodium channels open in response to?
What happens if the membrane depolarisation is maintained?
The sodium channel exit the open state and enter the inactivated state.
How many gates does the sodium channel have? Name them?
2 gates. 1. Activation gate 2. Inactivation gate
When does the inactivation gate close?
A delayed response to depolarisation.
Describe the stages of an AP in respects of the sodium channels?
1. RMP: activation gate closed. 2. Depolarising stimulus arrives at the channel. 3. Activation gate opens, sodium enters the cell. 4. Inactivation gate closed, sodium entry is stopped. 5. During depolarisation, two gates reset.
What is the amount of sodium current dependent on?
The magnitude of the depolarisation stimulus. The bigger the stimulus, the more channels are open
What do local anaesthetics do?
They prevent action potential propagation of nerve axons by blocking voltage-gated sodium channels.
What is the structure of the local anaesthetics and why is that important?
Small lipid soluble molecules. Important as they can cross the nerve sheath and cell membrane to reach site of action.
Name the 3 clinically used local anaesthetics?
Procaine, lignocaine and bupivacaine.
When can Local anaesthetics be used?
Only when the sodium channel is in the open state will the drug block from the inside. Also depolarisation enhances the blocking affect.
What does local anaesthetics do to the sodium inactivation process?
Seems to stabilise it.
TTX. Naturally occurring. Blocks nerve conduction and causes death by respiratory paralysis.
What does TTX do in the body?
Blocks the intercellular face of the voltage-activated sodium channels of nerve and skeletal muscle. Less sensitive in cardiac muscle.
What part of the P loop is important for the TTX to block the channel?
The glutamate. Mutate it to glutamine and TTX can no longer block the channel.
STX. similar to TTX. Blocks sodium channels at the same site.
mu-conotoxins (u-conotoxins) properties?
Small positively charged peptides Selectively blocks skeletal muscle sodium channels.
Inhibits the inactivation therefore the channels stay open longer.
Natural insecticide. Prolongs the activation and inhibits the inactivation of insect sodium channels.
b-scorpion toxins properties?
Activation of the channel at more negative potentials.
a-scorpion toxins properties?
Uncouples activation from inactivation. So when there is a prolonged depolarisation, the channel remains in its activated state.
The importance of the beta subunits in sodium channel auxiliary?
4 beta subunit genes (beta 1-4) Modulates channel gating allowing for rapid activation and inactivation
The importance of the immunoglobulin domain?
Binds extracellular proteins and be important determinants of channel localisation.
Localisation of the channels along the nerve cell?
Sodium channels at the node of ranvier. Potassium channel inside the axon.
How many sodium channel alpha subunits genes are there?
9 of them.
What alpha subtypes are predominately in the CNS? and why are these important?
1.1, 1.2 and 1.3 Sensitive to TTX.
What alpha subtypes are found in the PNS? and why are these important?
1.8 and 1.9 TTX- resistant
What channels are involved in the chronic inflammatory pain?
The TTX-resistant channels found in the PNS Na 1.8 and 1.9
Where is the sodium voltage gated channel 1.7 expressed?
Selectively expressed in dorsal root ganglion neurones.
What happens if you knock out Na 1.7?
Increased mechanical and thermal pain thresholds. Reduced inflammatory pain response. Unable to feel pain.
What happens if you mute sodium voltage gated channel 1.4?
Causes episodic and transient weakness or paralysis or relaxation defects.
Describe the properties of ventricular arrhythmia?
Congenital long QT syndrome and idiopathic ventricular fibrillation. Persistant inward sodium current causing abnormal repolarisation. Mutation if Na 1.5
Describe the properties of inherited epilepsy syndrome?
Found in mutations of Na1.1 and 1.2 Variable outcomes. May induce persistent sodium currents or altered voltage dependence of activation/inactivation. Causing enhanced excitability.