Channelopathies Flashcards
Cardiac Action Potential: Phase 0
What phase?
Ion channel
Process
Depolarization
Ion Channels Involved: Voltage-gated sodium channels (NaV1.5) - encoded by SCN5A gene
Process: channels open rapidly in response to a threshold voltage, allowing a rapid influx of sodium ions into the cell, causing rapid depolarization. This is the primary event that triggers the contraction of the heart.
Cardiac Action Potential: Phase 1
What phase?
Ion channel
Process
Initial Repolarization
Kv4.2 and Kv4.3
Process: After the peak of depolarization, Na+ channels close and transient K+ channels open briefly, allowing K+ to exit the cell. This causes a slight repolarization.
Cardiac Action Potential: Phase 2
What phase?
Ion channel
Process
Plateau Phase
Ion Channels Involved: Cav1.2 encoded by CACNA1C
L-type calcium channels (CaV1.2) and delayed rectifier potassium channels (IKr and IKs)
Process: Ca2+ enters the cell through L-type Ca2+ channels, while K+ continues to exit through delayed rectifier K+ channels. The influx of Ca2+ and efflux of K+ balance each other, leading to a plateau phase where the membrane potential is relatively stable.
Cardiac Action Potential: Phase 3
What phase?
Ion channel
Process
Repolarization
Ion Channels Involved: Kv11.1 (hERG) encoded by KCNH2 gene. Delayed rectifier potassium channels (IKr and IKs), inward rectifier potassium channels (IK1)
Process :L-type Ca2+ channels close, and K+ efflux continues through IKr and IKs channels. The cell repolarizes as the membrane potential returns to a more negative value.
Cardiac Action Potential: Phase 4
What phase?
Ion channel
Process
Resting Membrane Potential
Inward rectifier potassium channels (IK1)
Process: The membrane potential is maintained at a stable, negative value. IK1 channels help maintain this resting potential by allowing K+ to flow out of the cell, balancing the ionic environment.
State Key Ion Channels in Cardiac Physiology
Voltage-Gated Sodium Channels (NaV1.5): Rapid depolarization in Phase 0.
Transient Outward Potassium Channels (Ito): Initial repolarization in Phase 1.
L-type Calcium Channels (CaV1.2): Plateau phase in Phase 2.
Delayed Rectifier Potassium Channels (IKr and IKs): Repolarization in Phases 2 and 3.
Inward Rectifier Potassium Channels (IK1): Maintain resting membrane potential in Phase 4.
Briefly describe the whole cardiac action potential
Phase 0 (Depolarization): Rapid influx of Na+ through NaV1.5 channels.
Phase 1 (Initial Repolarization): Brief efflux of K+ through transient outward potassium channels (Ito).
Phase 2 (Plateau Phase): Balance between Ca2+ influx via L-type calcium channels (CaV1.2) and K+ efflux via delayed rectifier potassium channels (IKr and IKs).
Phase 3 (Repolarization): Continued K+ efflux via IKr, IKs, and IK1 channels.
Phase 4 (Resting Membrane Potential): Stabilized by IK1 channels, maintaining a negative resting potential.
Long QT Syndrome (LQTS)
Long QT syndrome (LQTS) is a cardiac disorder characterized by prolonged repolarization of the heart, leading to an extended QT interval on an electrocardiogram (ECG). This condition increases the risk of life-threatening arrhythmias, such as Torsades de Pointes.
LQTS Mechanisms: KCNQ1 (LQT1)
Function and mutation effect:
Function: Encodes the alpha subunit of the IKs channel.
Mutation Effect: Reduces IKs current, leading to delayed repolarization.
LQTS Mechanisms: KCNH2/hERG (LQT2)
Function and mutation effect:
Function: Encodes the alpha subunit of the IKr channel.
Mutation Effect: Reduces IKr current, leading to prolonged repolarization.
LQTS Mechanisms: SCN5A (LQT3)
Function and mutation effect:
Function: Encodes the NaV1.5 sodium channel.
Mutation Effect: Causes delayed inactivation of Na+ channels, resulting in prolonged depolarization.
Symptoms: Palpitations, syncope, ventricular tachycardia.
Clinical manifestations of LQTS
Symptoms: Syncope, seizures, sudden cardiac death.
Triggers of LQTS
Triggers: Physical exertion, emotional stress, medications.
KCNQ genes aren’t only in the heart - also in…
the inner ear and brain stem
Mutations to the SCN5A leads to
reduced inactivation and therefore persistent sodium influx
Mutations to KCNQ genes underlie what other congenital diseases?
- Deafness without cardiac affects
- Epilepsy and neurodevelopment
Blocking the Kv11.1 channel ….
Prolongs the cardiac action potential and Can lead to early after depolarisations
Prolonged Action Potential Duration = likelihood of early after depolarisations (EADs)
Kv11.1 (hERG encoded) has a wide external mouth.
It is blocked by:
anti-arrhythmics
Anti-histamine eg terfendadine
GI agents eg cisapride
Protease inhibitors eg
Anti-biotics eg erythromycin
Anti-depressants eg fluoxetine, citalopram
Anti-parasitic eg chloroquine
Anti-fungal eg ketoconazole.
Where are other ERG channels found?
Neurones
smooth muscle
uterus
bladder
Skeletal muscle disease: Myotonia
Myotonia is characterised by delayed relaxation following forceful contraction and is associated with repetitive action potential generation.
Mutations to SCN4a underlie many myotonias
NaV1.4 is important for?
transducing the nerve activation and stimulation of muscle by acetylcholine to contraction.
Mutations to SCN4a
Mutations to SCN4a lead to reduced inactivation or increased recovery from inactivation.
More sodium channel activity = prolonged contraction = less relaxation of the muscle
SCN4A function
Mutation Effect
Symptoms
Function: Encodes NaV1.4 sodium channels in skeletal muscle.
Mutation Effect: Causes sustained depolarization, preventing normal muscle relaxation.
Symptoms: Muscle stiffness, delayed relaxation after contraction, potential muscle weakness.
LQT2
LQT2 is associated with mutations in the KCNH2 gene, which encodes the hERG (human Ether-à-go-go-Related Gene) potassium channel. This channel is crucial for cardiac repolarization.
hERG Channel Properties
Function: Contributes to the IKr current, essential for phase 3 repolarization of the cardiac action potential.
hERG Channel Mutations
Mutations reduce IKr current, delaying repolarization and prolonging the QT interval.
Clinical Implications: Increased risk of arrhythmias like Torsades de Pointes.
Importance of hERG Screens in Drug Development
Drug-Induced QT Prolongation: Certain drugs can block hERG channels, leading to QT prolongation and increased risk of arrhythmias.
Regulatory Requirements: Screening for hERG activity is essential to prevent adverse cardiac effects from new drugs.
Screening Methods: In vitro and in vivo assessments of hERG channel activity, including patch-clamp studies and animal models.
