ion channels in health and disease Flashcards
lecture 7
What is channelopathy?
A disease or pathology arising from ion channel dysfunction, caused by abnormalities in ion channel subunits or regulatory proteins.
How many proteins are represented by ion channels in the genome?
Over 400 proteins, representing more than 1% of the genome
What are the two main causes of channelopathies?
- **Genetic: **Mutations in ion channel genes (e.g., SCN9A mutations)
- Acquired: Causes include drug/toxin exposure or autoimmune disorders.
Give examples of genetic and acquired channelopathies
Genetic: Cystic Fibrosis (CF), caused by CFTR gene mutations.
Acquired: Myasthenia Gravis, postoperative pain
What is the relationship between phenotype, genotype, and environment?
Phenotype (P) is the observable traits of an organism and results from the interplay of:
1. Genotype (G)
2. Environment (E)
3. Interaction between genotype and environment (GE)
P = G + E + GE
Define a phenotype and give examples.
Phenotype refers to the observable physical or behavioural traits of an organism.
Classic phenotypes: Height, BMI, eye colour
Disease phenotypes: Diabetes, Alzheimer’s Disease.
Other traits: Financial income, educational attainment
What is genetic linkage, and how is it studied?
Genetic linkage identifies genetic variants associated with specific traits:
1. Study families with a Mendelian inheritance pattern.
2. Genotype > 10,000 SNPs in each individual.
3. Identify “linked” SNPs near the trait locus
Explain the inheritance patterns of genetic channelopathies.
- Autosomal recessive: Loss-of-function (LOF) mutations (e.g., Cystic Fibrosis)
- Autosomal dominant: Gain-of-function (GOF) mutations (e.g., Huntington’s Disease, inherited erythromelalgia)
What is SCN9A, and why is it important in pain response?
SCN9A encodes the NaV1.7 sodium channel, which is highly expressed in sensory neurons of the dorsal root ganglia (DRG). It amplifies subthreshold stimuli and contributes to action potential generation. Mutations in SCN9A lead to various pain disorders.
Describe the effect of SCN9A mutations in inherited erythromelalgia (IEM)
Autosomal dominant mutation.
Leads to bilateral episodes of burning pain in extremeties, triggered by heat/exercise.
Mechanisms
- Lower activation threshold.
- Impaired fast inactivation.
- Enhanced ramp response.
What is paroxysmal extreme pain disorder (PEPD), and how is it caused?
Caused by autosomal dominant SCN9A mutations
Symptoms: Severe pain in rectal, ocular, and mandibular regions
Triggers: Chewing, heat
Mechanisms:
- Delayed inactivation
- Enhanced repetitive stimulation response
What is complete insensitivity to pain (CIP)?
Autosomal recessive SCN9A mutations lead to loss of function.
Results in a complete absence of paint sensation, often causing injuries.
Mutations are typically nonsense mutations.
How has SCN9A research advanced our understanding of pain?
Studies of rare monogenic pain disorders (e.g., IEM, PEPD, CIP) reveal mechanisms of pain and may inform broader pain responses and potential therapies.
What tools are used to study genetic variants associated with pain?
- Linkage Mapping: Family-based studies identifying Mendelian traits.
- Genome-Wide Association Studies (GWAS): Population-level studies genotyping 10,000+ SNPs to find associations with pain traits.
How do gain-of-function and loss-of-function mutations affect ion channels?
GOF mutations: increase channel activity (e.g., IEM)
LOF mutations: Decrease or abolish channel activity (e..g, CIP)
What are the subtypes of NaV channels, and their corresponding genes?
NaV1.1: SCN1A
NaV1.2: SCN2A
NaV1.3: SCN3A
NaV1.4: SCN4A
NaV1.5: SCN5A
NaV1.6: SCN8A
NaV1.7: SCN9A
NaV1.8: SCN10A
NaV1.9: SCN11A
How are toxins used in therapies targeting NaV channels?
Toxins can mimic binding to NaV channels, modulating their activity.
E.g., small molecules and botox are used in pain management strategies
How do genetic and environmental factors contribute to channelopathies?
Genetic: Mutations in ion channel genes (e.g., CFTR for cystic fibrosis)
Environmental: External factors like toxins, autoimmune reactions, or postoperative changes
What is the structure of NaV channels?
NaV channels consist of alpha subunits that form the pore, with subtype-specific genes (e.g. SCN9A fro NaV1.7)
How does NaV1.7 contribute to the action potential?
- Amplifies subthreshold stimuli
- Has a low activation threshold
- Exhibits fats kinetics
- Is TTX-responsive
What are some challenges in identifying genetic contributions to pain in the general population?
Monogenic pain disorders are rare.
Pain responses often require studying populations instead of families to capture genetic complexity.
How are mutations in SCN9A functionally classified?
- Gain of Function (GOF): Leads to excessive excitability (e.g., IEM, PEPD)
- Loss of Function (LOF): Results in reduced activity, as seen in CIP
How do association studies identify SNPs related to traits?
Measure the trait and genotype SNPs.
Fit statistical models for each SNP.
Identify SNPs with significant differences in allele frequency between groups.
What evolutionary factors might influence pain perception?
Differences in pain sensitivity across populations.
Connections to other senses, like smell, which could have conferred evolutionary advantages.
How does the CFTR mutation in cystic fibrosis affect ion channels?
Dysfunction in chloride ion influx disrupts water transport.
Leads to mucus accumulation, inflammation, and disease.
Mutations are functionally classified by their effects on the channel.
What is the impact of NaV1.7 mutations on symptom severity?
In IEM and PEPD:
- Increased excitability correlates with greater symptom severity.
- Changes include lowered activation thresholds and prolonged channel openings.
How do nature and nurture interplay in channelopathies?
Nature (genes): Inherited mutations (e.g., SCN9A, CFTR).
Nurture (environment): External factors like toxins or autoimmune diseases.
Phenotype = Genotype (G) + Environment (E) + Gene-Environment interaction (GE).
