Excitation Contraction Coupling

Question 1

What is inotropy?

Answer 1

Strength (ventricles)

Question 2

What is lucitropy?

Answer 2

Rate of relaxation (ventricles)

Question 3

What is chronotropy?

Answer 3

HR (SAN)

Question 4

What is dromotropy?

Answer 4

Delay at AVN

Question 5

What happens in phase 0 of ventricular AP?

Answer 5

• Rapid depolarisation due to Na channels
• INa flows into myocytes
• Cardiac Na channels differ from neuronal + are structurally similar to Ca channels

Question 6

What is LQTS3?

Answer 6

Functional mutation = Na channels take longer to switch off = prolonged AP

Question 7

What happens in phase 1 of ventricular AP?

Answer 7

• L-type Ca channels allows Ca into myocytes = ICa,L

- B adrenergic stimulation activates PKA phosphorylation of channel = increased Ca influx = stronger contraction

Question 8

What are the key currents due to K channel activity in phase 1,2,3,4?

Answer 8

• IK1 > channels maintain resting potential > phase 4
• Ito > channels inactivate rapidly > transient repolarisation (brings potential back down so Ca channels can function)
• IKr > hERG channels (associated with LQTS2)
• IKs (associated with LQTS1)

Question 9

What does B adrenergic stimulation activate?

Answer 9

PKA phosphorylation = increases IKs, IK1 & ICa,L

Increases outward K currents - IKs & IK1 MORE than inward ICa, L

Therefore repolarisation occurs earlier in action potential

Question 10

What is the role of ryanodine receptor channel (RyR2)?

Answer 10

• On SR = Ca release

- Channel opening increased by increased Ca2+ in dyadic cleft

Question 11

What is RyR2 channel opening inhibited by?

Answer 11

1. FKBP
   B adrenergic stimulation = FKBP phosphorylated + dissociates, relieving inhibition
2. Calsequestrin
   As Ca inside SR increases > binds to calsequestrin - relieves inhibition of RyR2

Question 12

How is relaxation during diastole achieved?

Answer 12

1. Na/Ca exchange - removes Ca across sarcolemma, maintains low Ca in diastole
2. Ca ATPase - removes Ca back to SR

Question 13

What can elevated Ca during diastole lead to?

Answer 13

Delayed after depolarisations = AP’s triggered at rest

Question 14

What is the role of Ca ATPases?

Answer 14

1. Sarcolemma
   - PMCA transports Ca OUT
   - Regulated by Calmodulin = enhances removal of Ca
2. Sarcoplasmic reticulum
   - SERCA transports Ca into SR
   - Regulated by Phospholamban - inhibits uptake Ca

Question 15

How does Phospholamaban regulate Lucitropy?

Answer 15

Adrenaline/noradrenalin > activates PKA = phosphorylation of phospholamban = formation pentamer which dissociates from pump = less inhibitory to SERCA

Promotes SR Ca re-uptake during B adrenergic stim = faster rate of relaxation

Question 16

How does Troponin I regulate Lucitropy?

Answer 16

Sympathetic stim = PKA phosphorylation of TnI = decreases myofilament Ca sensitivity + increased crossbridge = Ca off-load faster = faster relaxation

Question 17

What mechanisms underlie regulation of chronotropy?

Answer 17

• Tachycardia via increased cAMP binding to HCN4 channels

- Bradycardia via decreased cAMP binding to HCN4 channels + increased IKACh

Question 18

What happens in phase 4 of SAN AP?

Answer 18

• Mainly due to inward If
• Mostly via HCN4
• cAMP relieves auto-inhibition
• ICa,T = inward Ca through T-type
• INCX = inward via Na/Ca exchange
• IKrACh = outward via KIR channels = coupled to m2AChE and GiBY
• IK1 NOT PRESENT

Question 19

What are connexons?

Answer 19

• Formed of connexins

- Facilitate electronic current spread to adjoining myocytes

Question 20

Which connexins have low conductance?

Answer 20

30 + 45

In AVN = slow APs

Question 21

Which connexins have high conductance?

Answer 21

40 + 43

In Purkinje fibres = rapid AP’s