Channelopathies Flashcards
What are channelopathies and what are the 2 types?
Diseases caused by disturbed function of ion channel subunits or the proteins that regulate them
Congenital = resulting from a mutation
Acquired = resulting from autoimmune attack on an ion channel
What are mechanically-gated ion channels?
Channels which open/close in response to mechanical stimuli such as vibrations, sound waves, or pressure
What is cystic fibrosis and what are the 4 symptoms?
Autosomal recessive disease of secretory epithelia
Causes:
- Chronic lung disease
- Pancreatic dysfunction
- Elevated sweat electrolysis (salty sweat)
- Male infertility
What is Cystic fibrosis caused by and how does this ion channel function normally?
CF caused by mutation in the ion channel CFTR, which is a chloride ion channel
CFTR is regulated by the protein Kinase A and ATP binding, the binding of ATP and phosphorylation by Kinase A allows the CFTR channel to open
What are the 4 main causes of CF by mutation of the CFTR channel and how do they cause CF?
- Premature stop codon = forms a shorter protein that is likely to be degraded and won’t reach the cell membrane (won’t even make it to the ER)
- Misfolded protein = Protein will make it out of the ER, but won’t go through the Golgi apparatus, and so won’t reach the cell membrane
- Defective channel opening = CFTR channel reaches the cell membrane, but can’t open up to allow the ions to flow in
- Reduced conduction = CFTR reaches the cell membrane, but there is a reduced flow of ions through the channel and the flow is too slow for the ion channel to be effective
How are lung infections caused by CF? (3)
CFTR channel are required for the hydration of airway surface liquid
- The mucus layer need to be viscous in order to trap bacteria, but not too viscous so that the cilia can still move and clear away the bacteria-trapped mucus
- Stopping the movement of chloride ions through CFTR channels means that less water will diffuse into the liquid layer, and so the liquid layer will become more viscous, and eventually become too viscous for the cilia to move properly.
- This means that the mucus won’t be cleared, which will block the airways and make it harder to breathe. The trapped bacteria within the mucus won’t be swept away and so will cause lung infections
What causes patients with CF to have salty sweat?
In patients with working CFTR channels, the CFTR channels recapture Chloride ions back into epithelial cells from the blood and inhibits the ENal sodium channel, preventing secretion of sodium ions into the blood and reaching the sweat glands.
This maintains low levels of sodium and chloride ions in the sweat
When someone has CF, the CFTR channels won’t work properly, and so chloride ions will be lost into the blood and make their way to the sweat glands (no recapturing), causing hypersecretion of sodium into the blood and sweat glands
What are the 6 things available to mange CF symptoms and what do they do?
- Bronchodilator drugs = opens up the airways to allow the patient to breathe more easily
- Antibiotics = gets rid of infections caused by CF
- Steroids = reduces inflammation in the lungs
- Enzyme capsules = helps the digestion of food in the pancreas to prevent malnourishment
- High energy drinks to reduce malnourishment
- Mucolytics = reduce mucus viscosity
What is epilepsy?
What are convulsive and non-convulsive seizures?
What are seizures caused by?
Characterized by epileptic seizures which are the result of excessive and abnormal nerve cell activity
Convulsive seizures = twitching and loss of consciousness
Non-convulsive = decreased level of consciousness rather than loss of consciousness
Seizures are caused by imbalance of excitation and inhibition of nerve cells due to the failure of inhibitory neurotransmission
How does a nerve impulse trigger postsynaptic nerves? (2)
Nerve impulse causes membrane depolarisation which opens voltage gated calcium channels, allowing an influx of calcium into the presynaptic cells
This influx of calcium triggers the release of neurotransmitters across the synapse, which then bind to channels on the postsynaptic nerve to open them
What are Ionotropic glutamate receptors, what do they do and what are 2 examples of them?
Excitatory receptors found on the postsynaptic membrane
Examples = NMDA and AMPA
They are ligand-gated ion channels which open when glutamate binds.
- When glutamate binds, they open up and allow a flow of positive Na+ and Ca2+ ions into the postsynaptic cell, which makes the inside of the cell more positive.
- This depolarises the postsynaptic membrane and excites the nerve cell
What are GABA A receptors and what do they do?
Inhibitory receptors which are Ligand gated chloride channels found on the postsynaptic membrane
When GABA molecules bind, the channels allow the flow of negative Cl- ions into the postsynaptic cell, making the inside of the cell even more negative
This causes hyperpolarisation if the postsynaptic membrane, therefore inhibiting the activity of the postsynaptic nerve cell (this counters excitatory synaptic inputs)
What are GABA B receptors and how do they work?
G-protein coupled metabotropic receptors (not ion channels)
When GABA binds to the receptor, G-proteins are activated which activates potassium channels and inhibits Calcium channels
This results in more K+ ions flowing out of the cell and less Ca2+ ions flowing into the cell, making the inside of the cell more negative
Causes hyperpolarisation, so inhibitory (same as GABA A)
What is the structure of GABA A receptors and what 2 subunit mutations are linked to epilepsy, including which type of epilepsy they are linked to? (1 + 2)
Pentameric (5 subunits) transmembrane receptor
Composed of 2 alpha1, 2 Beta2 and one gamma2 subunits
Mutations in the gene encoding the alpha1 subunit is linked to the autosomal dominant form of juvenile myoclonic epilepsy (JME)
Mutations in the gene encoding the gamma2 subunit have been associated with febrile seizures in children absence epilepsy (CAE) and generalised epilepsy
What is the basic structure of sodium voltage gated channel?
Which subunit is different in different types of tissue?
Which subtypes of sodium channels are present in which tissues? (9 subtypes, 4 systems)
Which sodium channel subtype is associated with epilepsy and why?
All have 5 similar domains forming the functioning channel
Alpha subunit is expressed in/ at different levels in different tissues
- Nav1.1, 1.2, 1.3, and 1.6 expressed in CNS nerves
- Nav1.4 expressed in skeletal muscle
- Nav1.5 expressed in the heart
- Nav1.7, 1.8, and 1.9 expressed in the peripheral nervous system
Nav1.1 related to epilepsy as it is highly expressed in GABAergic inhibitory neurons
What are the 3 steps of generating the nerve impulse?
What do calcium channels do with the nerve impulse?
- Resting state = All Na+ and K+ channels are closed
- Depolarising phase = Na+ channels open to allow the flow of Na+ ions into the cell to create the action potential
- Repolarising phase = Na+ channels are inactivated and K+ channels open to allow the flow of K+ ions out of the cell to repolarise the membrane, ready for another wave of depolarisation to occur
Calcium channels transmit the nerve impulse to trigger the release of neurotransmitters
Diagram on summary sheet/jotter
What is JME, when does it usually begin, and what gender is it more common in?
What is it caused by?
Juvenile Myoclonic Epilepsy - begins around puberty
More common in girls than boys
Caused by mutations in the GABARA1 alpha1 subunit of GABA A receptor - impairing the trafficking of GABA A receptors to the cell membrane, so GABA A receptors aren’t present on the postsynaptic membrane
This reduces the ability of the postsynaptic neuron to receive inhibitory inputs from GABA molecules which results in the postsynaptic nerve being overexcited/active which causes seizures
What is the main treatment available for JME and what does it do?
What are the 2 limitations to this?
When in the day are seizures most likely to occur?
Antiseizure drugs like Valproic acid
Valproic acid decreases the breakdown of GABA molecules, increasing GABA concentrations
This increases the chance of inhibition occurring (as could be the odd GABA receptor that made it to the membrane)
This limits the onset of seizures
Limitations:
- Can’t use in pregnant women as can cause seizures
- Treatment is lifelong, risk of relapse if treatment is discontinued (have to take it their whole life)
In the morning when there is greater excitation
What is SMEI, what is another name for SMEI, and when does it usually begin?
What is it caused by? (4 steps)
Severe myoclonic epilepsy of infancy - occurs in first year of life
Also called Dravet syndrome
First seizure usually associated with a fever
- Caused by mutation in the SCN1A gene which codes for the Nav1.1 ion channel alpha subunit
- This causes loss of Nav1.1 function, resulting in impaired action potential firing in GABAergic inhibitory neurons, as these neurons are most reliant on Nav1.1 to generate action potentials
- This prevents the release of GABA across the synapse and prevents GABA from binding to GABA A and GABA B receptors on the postsynaptic membrane
- This reduces the inhibitory affects, causing hyperexcitation of the postsynaptic nerve which leads to seizures
What are the 3 treatments that can be used for SMEI epilepsy, what do they all do roughly , and in what type of patients would each treatment be used?
- Anti-epileptic drugs (AEDs) - used in all patients. Doesn’t cure epilepsy, but they all work to either dampen down excitation or increase inhibition (increase opening of GABA A receptors, or block Ca channels to prevent neurotransmitter release etc.)
- Neurosteroid treatments used in women who have increased seizures during periods of low progesterone in the menstrual cycle
- Small number of patients can be prescribed medicinal cannabis oil to reduce the frequency of seizures
What are ATP-sensitive potassium ion channels?
What are they important in regulating? (roughly)
Channels that are closed when ATP is bound (inhibited by ATP)
Important for glucose homeostasis as it helps to regulate insulin secretion
How does low metabolism decrease the amount of insulin released from cells? (4 steps)
- Low metabolism = less ATP is being released into the cell, so less ATP is binding to potassium channels and inhibiting them, meaning that potassium channels stay open
- This means that more potassium ions can flow out of the cell down their conc. gradient, making the inside of the cell more negative, which hyperpolarises the cell membrane (K+ efflux)
- Since the cell membrane remains polarised (isn’t depolarised), voltage calcium channels remain closed, meaning calcium ions don’t flow into the cell (no calcium influx)
- No calcium influx means that no insulin is released
How does high metabolism increase the amount of insulin released from cells? (4 steps)
- High metabolism = more ATP is being released into the cell, so more ATP is binding to potassium channels and inhibiting them, meaning that potassium channels are being closed, preventing K+ flow out of the cell
- This makes the inside of the cell more positive, causing the membrane to be depolarised
- This depolarisation opens up calcium ion channels, allowing an influx of calcium ions into the cell
- This calcium influx causes release of insulin out of the cell
What is neonatal diabetes and what does this result in?
How does the mutation arise and what does the mutation cause to happen? (3 steps)
What is the treatment available for this?
Reduced insulin secretion resulting in reduced birth weight and hyperglycaemia
Mutations arise spontaneously (de novo, neither parent has the mutation)
- Mutant potassium channel is less sensitive to inhibition by ATP binding
- This leads to potassium channels staying open, causing an efflux of K+ ions out of the cell, so membrane remains hyperpolarised
- This means that Ca2+ channels won’t open, so no Ca2+ influx and therefore no insulin release
Treatment = sulphonyl urea drugs work to inhibit the potassium ion channel and prevent potassium efflux
