Channelopathies

Question 1

Cardiac Action Potential: Phase 0
What phase?
Ion channel
Process

Answer 1

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.

Question 2

Cardiac Action Potential: Phase 1
What phase?
Ion channel
Process

Answer 2

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.

Question 3

Cardiac Action Potential: Phase 2
What phase?
Ion channel
Process

Answer 3

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.

Question 4

Cardiac Action Potential: Phase 3
What phase?
Ion channel
Process

Answer 4

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.

Question 5

Cardiac Action Potential: Phase 4
What phase?
Ion channel
Process

Answer 5

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.

Question 6

State Key Ion Channels in Cardiac Physiology

Answer 6

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.

Question 7

Briefly describe the whole cardiac action potential

Answer 7

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.

Question 8

Long QT Syndrome (LQTS)

Answer 8

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.

Question 9

LQTS Mechanisms: KCNQ1 (LQT1)
Function and mutation effect:

Answer 9

Function: Encodes the alpha subunit of the IKs channel.
Mutation Effect: Reduces IKs current, leading to delayed repolarization.

Question 10

LQTS Mechanisms: KCNH2/hERG (LQT2)
Function and mutation effect:

Answer 10

Function: Encodes the alpha subunit of the IKr channel.
Mutation Effect: Reduces IKr current, leading to prolonged repolarization.

Question 11

LQTS Mechanisms: SCN5A (LQT3)
Function and mutation effect:

Answer 11

Function: Encodes the NaV1.5 sodium channel.
Mutation Effect: Causes delayed inactivation of Na+ channels, resulting in prolonged depolarization.

Symptoms: Palpitations, syncope, ventricular tachycardia.

Question 12

Clinical manifestations of LQTS

Answer 12

Symptoms: Syncope, seizures, sudden cardiac death.

Question 13

Triggers of LQTS

Answer 13

Triggers: Physical exertion, emotional stress, medications.

Question 14

KCNQ genes aren’t only in the heart - also in…

Answer 14

the inner ear and brain stem

Question 15

Mutations to the SCN5A leads to

Answer 15

reduced inactivation and therefore persistent sodium influx

Question 16

Mutations to KCNQ genes underlie what other congenital diseases?

Answer 16

• Deafness without cardiac affects
• Epilepsy and neurodevelopment

Question 17

Blocking the Kv11.1 channel ….

Answer 17

Prolongs the cardiac action potential and Can lead to early after depolarisations

Prolonged Action Potential Duration = likelihood of early after depolarisations (EADs)

Question 18

Kv11.1 (hERG encoded) has a wide external mouth.
It is blocked by:

Answer 18

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.

Question 19

Where are other ERG channels found?

Answer 19

Neurones
smooth muscle
uterus
bladder

Question 20

Skeletal muscle disease: Myotonia

Answer 20

Myotonia is characterised by delayed relaxation following forceful contraction and is associated with repetitive action potential generation.
Mutations to SCN4a underlie many myotonias

Question 21

NaV1.4 is important for?

Answer 21

transducing the nerve activation and stimulation of muscle by acetylcholine to contraction.

Question 22

Mutations to SCN4a

Answer 22

Mutations to SCN4a lead to reduced inactivation or increased recovery from inactivation.
More sodium channel activity = prolonged contraction = less relaxation of the muscle

Question 23

SCN4A function
Mutation Effect
Symptoms

Answer 23

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.

Question 24

LQT2

Answer 24

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.

Question 25

hERG Channel Properties

Answer 25

Function: Contributes to the IKr current, essential for phase 3 repolarization of the cardiac action potential.

Question 26

hERG Channel Mutations

Answer 26

Mutations reduce IKr current, delaying repolarization and prolonging the QT interval.
Clinical Implications: Increased risk of arrhythmias like Torsades de Pointes.

Question 27

Importance of hERG Screens in Drug Development

Answer 27

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.