Lecture 23; Channelopathies Flashcards
What are the properties of ion channels?
Ion channels have several important properties:
- Conduct ions
- Recognize and select specific ions
- Open and close in response to specific electrical, mechanical or chemical signal
- Provide a large flow of ionic current
What does neuronal signalling depend on and what supplies this?
Neuronal signalling depends on rapid changes in electrical potential across nerve cell membranes.
Rapid changes in membrane potential are mediated by ion channels, a class of integral membrane proteins found in all excitable cells of the body.
Classify the types of ion channels;
Most channels are regulated or gated:
- Voltage-gated
- Ligand-gated
- Mechanically gated (pressure or stretch)
Also; Resting channels (maintains RMP in absence of signal)
What can ion channels be grouped into?
Gene families
i. e
- Ligand gated channel (Ach)
- Gap Junction Channel
- Voltage gated channel (Na)
Each subunit forming the channels are different but similar AA sequence.
Whats responsible for APs?
• Voltage-dependent sodium (VDSC) and voltage-dependent potassium (VDKC) channels are responsible for the action potentials.
Where are voltage gated ion channels found and what ions are conducted?
- All excitable cells contain voltage-sensitive ion channels
* Channels selective for sodium, calcium, potassium or chloride; other less selective ion channels
What does synaptic transmission depend on?
Synaptic transmission depends on ligand-gated ion channels
What are the main excitatory and inhibitory neurotransmitters?
The main excitatory transmitter in the brain and spinal cord is glutamate, and the most common transmitters in the CNS that activate inhibitory responses are GABA and glycine.
What are the main ligand gated ion channels in the brain?
- nACh receptor, GABA and glycine receptors, 5-HT3 receptors
- Glutamate receptors
- ATP-gated ion channels
What are the types of glutamate receptors?
The glutamate receptors:
• the ionotropic receptors and
• the metabotropic receptors. (can be excitatory or inhibitory)
What are the three main types of glutamate inotropic receptors?
NMDA
AMPA
Kainate
What are the neurotransmitters of IPSP in spinal motor neurons?
Inhibitory postsynaptic potentials in spinal motor neurones and most central neurones are generated by the inhibitory neurotransmitters, GABA and glycine.
What are the types of GABA receptors?
GABA is a major inhibitory transmitter in the brain and spinal cord. Receptors: GABA(a), GABA(b) and GABA(c).
Gaba(a,c) gate Cl channels
Gaba(b) is a metabotropic receptor that activates secondary cascades
What are channelopathies?
Mutations of ion channel genes that alter the function of ion channels and result in disease
Can also be caused by autoimmune mechanisms
Affect skeletal muscles, brain, heart, kidney, and the inner ear; significant disease burden
When do channelopathies occur and effect an individual?
Present early in life
Cause periodic attacks, often with remissions between attacks; progressive impairment
What channels are channelopathies associated with?
Associated with all four major types of voltage-gated ion channels (sodium, calcium, potassium, chloride), ligand-gated ion channels (glycine, GABA, nAChR) and connexin hemichannels
What can cause channelopathies?
Arise from the interaction of genetic and environmental influences
What can channelopathies affect?
Can affect the entire nervous system
Cause paroxysmal disturbances of brain, spinal cord, peripheral nerve or skeletal muscle function
Pathologies include epilepsy, movement disorders, headache, pain, ataxia, night blindness
What are diseases caused by Ca channelopathies?
- FHM, familial hemiplegic migraine
- EA2, episodic ataxia type 2
- CNSB, congenital stationary night blindness
What is Familial Hemiplegic Migraine?
Familial hemiplegic migraine (FHM)
Migraine attacks that typically last 1-3 days
Patients experience severe headaches and vomiting
Accompanied by reversible unilateral weakness (hemiplegic) and visual, sensory or speech difficulties
Close family member must be diagnosed too
Cause by Ca channel mutations
What potential channels have mutations in FHM?
Ca 2.1
Na1.1
FHM2
What happens when there is a mutation in Ca2.1 in FMH?
- Allows channels to become active at a lower membrane potential (-ve)
= Excitatory inhibitory imbalance
What happens when there is a mutation in Na1.1 in FMH?
Affects Na1.1 (inhibitory presynaptic GABA neuron)
Mutation = No depolarisation and GABA release.
What happens when there is a mutation in FHM2?
Decrease glutamate reabsorption therefore glutamate accumulation
What are the signs of episodic ataxia type 2?
Recurrent attacks of abnormal limb movements and severe ataxia (discoordination)
Accompanied by vertigo, nausea and headache
Attacks last for a few hours
Attacks precipitated by emotional stress, exercise or alcohol
What is the mutation in EAT2?
The mutations cause Ca2+ channels to be truncated at various sites, which prevents normal assembly of Ca2+ channels in the membrane
There are currently 19 mutations associated with EA2, and all result in decreased current through Ca2+ channels
What causes the ataxia in EAT2?
Ataxic gait
• Ataxia is due to misfiring of Purkinje cells in the cerebellum
What are the symptoms of CSNB?
A rare X-linked disorder affecting retina and causing night blindness, decreased visual acuity, myopia, nystagmus and strabismus
What are the types of CSNB?
CNSB1 caused by mutations in the gene NYX, which encodes a protein nictalopin involved in synaptic transmission
CNSB2 caused by truncation of Ca2+ channels
What causes the abnormal retinal function in CSNB?
Abnormal retinal function arises from decreased Ca2+ currents and neurotransmitter release form photoreceptors
What are diseases caused by abnormal Na channels?
GEFS, generalised epilepsy with febrile seizures
Who does GEFS affect?
A benign self-limiting condition that affects ~5% of children
Begins in infancy and often disappears before puberty
GEFS+ can persist beyond early childhood (i.e., 6 years of age).
What happens in GEFS?
Generalized epilepsy with febrile seizures plus (GEFS+) is a syndromic autosomal dominant disorder where afflicted individuals can exhibit numerous epilepsy phenotypes such as severe myoclonic epilepsy or temporal lobe epilepsy.
What is mutated in GEFS+?
Defects on chromosome 2 (encodes α subunit of voltage-gated Na+ channel) or chromosome 19 (encodes β subunit of Na+ channel)
Mutations of at least 4 ion channel genes cause GEFS+
Mutations cause a slowing of Na+ channel inactivation
Whats a condition that arises from nAch mutation?
Autosomal dominant nocturnal frontal lobe epilepsy
gets confused with someone having a nightmare
What is Autosomal dominant nocturnal frontal lobe epilepsy characterised by?
Causes frequent violent seizures during sleep
Usually starts within the second decade of life
What is the mutation in Autosomal dominant nocturnal frontal lobe epilepsy
Rare genetic syndrome caused by mutations in at least two subunits of the neuronal nAChR.
Presynaptic inhibition of GABA release resulting in hyperexcitability
Malfunction in thalamo-cortical pathways (important for sleep and generation of seizures)
Describe the GABA ion channel
Five subunits
a,a,b,b,g
What does a mutation in the gamma subunit of GABA result in?
Mutations in the γ2 subunit, encoded by GABRG2, have been identified in several families with GEFS + or related syndromes.
What does mutations in the a1 subunit result in?
A family with juvenile myoclonic epilepsy with a mutation in GABRA1, which encodes the α1 subunit.
What does mutations in the b3 subunit result in?
A few families with childhood absence epilepsy with a mutation in GABRB3, which encodes the β3 subunit.
What do mutations in GABA receptors cause?
These mutations impair GABAA receptor function (trafficking, synaptic localisation, kinetics)
What do mutations in glycine ion channels contribute to?
Contribute to fast inhibition in the spinal cord and brainstem
Disorders underlie familial hyperekplexia
What are the common mutations in glycine receptors?
Mutations of GLRA1 and GLRBwhich encode α1 and β1 subunits respectively
What are the symptoms of glycine receptor mutations?
Disorder manifests as exaggerated startle response to tactile, visual or acoustic stimuli in infancy
Sterotypical spasms consisting of forced closure of the eyes, extension of the arms, body stiffness, and apnoea (life threatening)
The spasms can be attenuated with benzodiazepines
Why do so many channelopathies have paroxysmal (infrequent) attacks?
A possible explanation is that neuronal excitability is tightly regulated and the changes of expression levels or function of one channel lead to compensatory changes in other ion channels.
However, normal function is vulnerable to various stressors in patients with channelopathies, implying a smaller safety factor before a paroxysm is generated.
What dopes time dependant presentation of channelopathies indicate?
Time-dependent presentation of disease signs and symptoms may reflect the presence of compensatory mechanisms early in life which suppress clinical manifestations.
Later in life, the protective effects of these compensatory mechanisms are overcome, due either to cumulative events, maturational switching of splice isoforms, or of modified genes and their products.
What do autoimmune channelopathies affect?
Autoimmune channelopathies include disorders of the peripheral, autonomic and central nervous system
Some antibodies may bind to the agonist site of ion channel pore affecting the opening of the channel.
What are Autoimmune channelopathies of the nervous system?
Neurological disorders associated with autoantibodies against ligand-gated or voltage-gated ion channels
Autoimmune channelopathies can occur with or without cancer
Paraneoplastic conditions are defined as neurological diseases secondary to the presence of tumour, but not caused by a tumour.
They result from the immune response generated against the tumour, and the resulting T cells and antibodies cross-react with neuronal tissue.
What is Lambert-Eaton Myasthenic Syndrome (LEMS)?
Associated with autoimmunity to voltage-gated calcium channels (VGCC)
Up to 60% of cases associated with small cell lung cancer
LEMS usually precedes tumour diagnosis by several months or years
Presented with progressive weakness affecting the legs more than the arms; less fatigability than in MG
In LEMS what is affected?
LEMS is a presynaptic disorder of neuromuscular junction resulting in depletion of VGCC and reduced calcium influx into the nerve terminal and impaired release of ACh.
What is Acquired neromyotonia (NMT)?
Associated with autoimmunity to voltage-gated potassium channels (VGKC)
These antibodies reduce potassium channel function, resulting in insufficient muscle relaxation.
What is affected in NMT?
Presents with fasciculation (muscle twitch), painful cramps, stiffness, and hyperhydrosis (abnormally increased perspiration)
The limb and trunk muscles most commonly affected
Often associated with other autoimmune disorders (MG, rheumatoid arthritis, SLE, diabetes)
NMT patients improve with plasma exchange and other immunosuppressive treatments
What is Encephalitis associated with AMPA receptor antibodies?
Autoimmunity to AMPA type GluR3 receptor has been associated with Rassmusen’s encephalitis (RE).
RE is a severe form of childhood epilepsy usually restricted to one hemisphere. It leads to marked cognitive decline.
What happens in Encephalitis associated with AMPA receptor antibodies??
Associated with inflammatory and degenerative changes in the cerebral cortex
There is accumulating evidence that RE is a T cell mediated disorder, and GluR3 antibodies may be secondary to the neuronal damage
What is Epilepsy associated with GABA receptor antibodies?
Antibodies to G protein-coupled GABAB receptor reported in some patients with seizures
Autoantibodies recognise the β1 subunit of the metabotropic GABAB receptor
What happens in Epilepsy associated with GABA receptor antibodies??
Disruption of this inhibitory receptor is associated with seizures and memory dysfunction.
EEG findings consistent with limbic dysfunction.
Half of the cases also have a small cell lung cancer.
Most patients respond to immunotherapy and cancer treatment
