Cardiac Arrythmias

Question 1

CALCIUM CHANNELS

1. which subunit forms the channel?
2. which subunits form the regulators?
3. name 5 Ca_v channels that are expressed in the heart
4. How do Ca_v channels differe from one another?

Answer 1

1. α1
2. α2, β1-4 and δ
3. Ca_v 1.2, 2.1, 3.1, 3.2 and 3.3
4. in terms of voltage dependence and pharmacological properies

Question 2

1. what type of calcium channels are Ca_v1.2? What does this mean?
2. what is Ca_v1.2 gated by?
3. what is Ca_v1.2 encoded by?
4. how many alternative splicing loci does Ca_v1.2 have? How many NORMAL functioning splice varients does this produce?
5. in which domains does splicing occur?
6. what are some splice varients associated with?
7. where are Ca_v channels expressed? What do they interract with?
8. name the 2 types of inactivation that Ca_v channels display

Answer 2

1. L type. Means they have long lasting activation
2. high voltage
3. CACNA1C
4. 12. produces 42 normal functioning splice varients
5. C and N termini, and between S4 and S5
6. diversity of biophysical properties
7. in T tubules near sarcoplasmic reticulum. Coupled to ryanodine receptors
8. voltage dependent inactivation and calcium dependent inactivation.

Question 3

1. Name 4 symptoms of Timothy Syndrome
2. Name 4 facial features of Timothy Syndrome patients
3. What type of syndrome is Timothy Syndrome
4. what is QTc? What is the value of it in suffers of Timothy Syndrome
5. give 2 characteristics of an ECG of a Timothy Syndrome patient

Answer 3

1. arrythmias, congenital heart disease, syndactyly, immune deficiency and a strong correlation with autism
2. round face, flat nasal bridge, thin upper lip and small upper jaw.
3. Long QT syndrome
4. QT/√RR. 650msecs
5. 2:1 atrioventricular block (2 P waves to every QRS complex); alternating T wave polarity when HR is increased (indication of a severe repolarising defect)

Question 4

1. what was found in 13 Timothy Syndrome patients when they were genetically screened?
2. what suggests that the glycine at position 406 is critical for Ca_v function?
3. what is a mosaic? How can it account for offspring suferring from the condition but not their parents?

Answer 4

1. the G406R mutation, which is responsible for producing a novel alternative splicing loci, resultng in a a novel Ca_v1.2 splice varient
2. it is conserved across all varients of Ca_v in humans and Ca_v in other organisms
3. an organism that carries cells wit a variable genotype in one or more loci. This means a mutation may be harbored in some tissues, or even the germline. If the mutation is only harbored in the germline, then offspring will be effected but the parent wont.

Question 5

1. what is the characteristics of WT I_Ca currents at high voltages?
2. what happens to WT I_Ca currents following inactivation and why?
3. did the G406R mutation impact inactivation or activation?
4. why was barium used to measure currents?
5. when barium was used, what was the difference between WT and G406R channel inactivation?
6. How does the G406R varient therefore cause a hyperpolarisation defect?

Answer 5

1. lower/small
2. increase, due to the relief of Ca dependent inactivation
3. inactivation
4. because it still produces a current through Ca_v channels, however it doesn’t contribute to Ca dependent inactivation
5. WT channels showed some inactivation, while G406R channels showed no inactivation.
6. There is a large impact on voltage dependent inactivation. Therefore Ca_v channels don’t inactivate in response to a change in Vm, resulting in a prolonged plateau phase which delays inactivation.

Question 6

Short QT Syndrome

1. name 3 channels in which GOF mutations are found.
2. name 3 channels in which LOF mutations are found.
3. name 3 characteristics of an SQT ECG trace

Answer 6

1. KCNH2, KCNQ1, KCNJ2
2. CACNA1C, CACNB1B
3. accentuated J wave, ST elevation and other complex ECG changes

Question 7

Name 3 mutations in calcium channels that cause SQT

Answer 7

1. s418L in CACNB2b
2. G490R in CACNA1C
3. A39V in CACNA1C

Question 8

1. what is the characteristic of currents of A39V and S418L mutants?
2. what is the characteristic of currents of G490R mutants?
3. where are WT channels expressed?
4. where are S481L and G490R mutants expressed? What does this imply?
5. where are A93V mutants expressed? What does this imply?

Answer 8

1. smaller currents than WT
2. no currents at all
3. at the cell surface
4. at the cell surface. These mutants are likely to impact gating
5. in the perinuclear region. The mutation impacts the trafficking of the channel (studies to see if the channel is functional at the channel?)