β-AR effect on HR and CO

Question 1

Which Receptor?

Answer 1

• β1

- β2 KO mice display normal response to catecholamines

Question 2

PMC currents

Answer 2

• cAMP increases HCN conductance directly, raising If
• PKA raises Ca IC and K OC
• Re/depolarisation both happen faster
• Faster PM rhythm

Question 3

Ca handling PKA targets

Answer 3

• LTCC
• SR-AKAPs (to enhance RyR)
• PLB (SERCA)
• All increase CICR- Ca binds to TnC

Also
- MLCK (also induced by Ca-CaM binding)

Question 4

Stroke Volume

Answer 4

• SERCA (relief of PLB) induction causes faster, more effective uptake of Ca into the SR

Question 5

Ca sensitivity PKA target

Answer 5

• TnI (inhibitor)

- TnI.Pi lowers Ca-sensitivity by disinhibiting tropomyosin

Question 6

Regulation and Antagonism

Answer 6

Magnitude, time and space

Spacial
- phosphodiesterases degrade errant cAMP to compartmentalise the signal intracellularly

Muscarinic Phosphatase Inhibition
- phosphatases dePi PKA targets (TnI, PLB)

Question 7

Lusitropy

Answer 7

• PKA Pi TnI
• Pi.TnI allows TnC.Ca to dissociate more easily
• TnC.Ca dissociation is the rate limiting factor of relaxation

Question 8

MyBPC

• Position and role
• βA-R stimulation and disease

Answer 8

• Part of thick filament
• Interacts with actin +/or myosin
• Controls stretch-activation rate
• 3 Pi sites for PKA
• Severe HF phenotype if deleted in transgenic mice

Question 9

Arrhythmia

Answer 9

• Loss of feedback control of stimulus
• Excess βA-R stimulation
• High levels of Pi
• Ca overloading
• Spontaneous beating and focal arrhythmia

Question 10

HF

Answer 10

• βA-R inactivated or internalised
• Adrenergic signal is not transduced
• Low levels of Pi

Question 11

Familial DCM mutation and response to βA-R stimulation

Answer 11

• Mutation in TTN
• PKA signal is normal
• Contraction functionally uncoupled from Pi

Question 12

Takotsubo (stress) CM

Answer 12

• Ad surge in response to stress
• β2-R switch to Gi coupling
• Depress contraction