Lec 9 Cellular Regulation

Question 1

What is I[K,Ach]?

Answer 1

Acetylcholine-sensitive K current

Question 2

What is HCN?

Answer 2

Hyperpolarization-activated, cyclic nucleotide-gated

- another name for funny current

Question 3

What is positive chronotropy?

Answer 3

faster heart rate

Question 4

What is positive inotropy?

Answer 4

stronger contraction

Question 5

What is positive dromotropy?

Answer 5

faster cell to cell conduction

Question 6

What is positive lusitropy?

Answer 6

faster relaxation

Question 7

How does parasympathetic stimulation affect HR?

Answer 7

decrease HR

Question 8

How does parasympathetic inhibition affect HR?

Answer 8

increase HR

Question 9

What does propanolol do?

Answer 9

B-adrenergic receptor blocker

thus inhibits sympathetic

Question 10

What does atropine do?

Answer 10

Muscarinic Acetylcholine receptor blocker

thus inhibits parasympathetic

Question 11

Does parasympathetic or sympathetic inhibition have a bigger effect on HR?

Answer 11

• parasympathetic inhibition has a much stronger effect [increases HR by a lot]
• sympathetic inhibition decreases HR but not by as much

Question 12

Is resting HR dominated by sympathetic or parasympathetic?

Answer 12

parasympathetic

Question 13

What are two consequence of parasympathetic tone of HR?

Answer 13

1. inhibition of parasympathetic has greater effect than inhibition of sympathetic
2. stimulation of sympathetic has greater effect than stimulation of parasympathetic

Question 14

What is the difference in time course between parasympathetic and sympathetic stimulation?

Answer 14

• parasympathetic stimulation is faster and goes away faster

Question 15

What kind of cholinergic receptors are in SA and AV node? What important kind are missing?

Answer 15

• Muscarinic Ach receptors present

- Nicotinic Ach receptors absent

Question 16

How is parasympathetic effect mediated [pathway of action]? What secondary messenger involved?

Answer 16

1. ACh released from nerve into synaptic cleft
2. ACh binds G-protein coupled muscarinic receptor
3. GPCR inhibits adenylyl cyclase [AC] so get decrease in cAMP, decrease protein kinase A [PKA]

Question 17

What innervates ventricular muscle?

Answer 17

sympathetics ONLY

Question 18

What is effect of G-beta-gamma subunit in SA node?

Answer 18

• dissociates from M receptor at activation
• binds and open acetylcholine-sensitive K current [I(K,ACh)]
• cAMP independent effect

Question 19

What activates I(K,Ach)?

Answer 19

G-b-gamma subunit of GPCR that dissociated from M receptor in presence ACh

Question 20

What type of current is Ikach?

Answer 20

• generates outward, repolarizing current
• opposes action of funny current so it will take longer for the membrane to reach the threshold necessary for activation of L-type current
• this delay makes SA nodal firing and HR slower

Question 21

What is affect of parasympathetic stimulation on AV node?

Answer 21

• decrease in PKA activity

- slower conductance [negative dromotropy]

Question 22

Where in heart are parasympathetic effects vs sympathetic effects acting in heart?

Answer 22

parasympathetic: SA, AV, atria
sympathetic: SA, AV, ventricle

Question 23

What is effect of sympathetic stimulation [pathway]?

Answer 23

• via Epi/NE
• activates Gs coupled B adrenergic receptors
• activates adenylate cyclase –> activated cAMP –> more Protein kinase

Question 24

What is sympathetic effect on funny current? How?

Answer 24

• sympathetic stimulation activates funny current directly via cAMP
• funny current = depolarizing Na current so increasing it increases speed of SA node firing

Question 25

Does funny current activation by cAMP require phosphorylation?

Answer 25

No - no phosphorylation or PKA involved, just direct effect from cAMP

Question 26

How does increased funny current increase HR?

Answer 26

less time required to depolarize membrane

Question 27

How does sympathetic affect AV?

Answer 27

• increased AV

- positive dromotropy [faster conduction]

Question 28

What mech explain why SA node effect by parasympathetic is faster than sympathetic?

Answer 28

for parasympathetic: G protein By subunit right in membrane and directly affects ACh sensitive K current also in membrane
= close together, easy to turn on, few intermediate steps

for sympathetic: Activation I[f] by increased cAMP requires adenylyl cyclase intermediate
= AC is rate limiting step

Question 29

What 2 effects does sympathetic stimulation have on ventricle?

Answer 29

• positive inotropy [stronger contraction]

- positive lusitropy [faster relaxation]

Question 30

What is isoproterenol?

Answer 30

B-adrenergic agonist

stimulates sympathetic

Question 31

What are 4 downstream targets of B-adrenergic stimulation in ventricle?

Answer 31

1. L-type Ca channel
2. phospholamban
3. RyR
4. Troponin I

Question 32

Effect of B stimulation on L-type Ca current?

Answer 32

• get shift to left in current vs voltage graph means easier to turn on voltage gated Ca channels [fully open at lower voltage]
• B stimulation –> PKA –> L type Ca phosphorylation
• have much more Ca entry with each AP
• higher Ca –> higher SR Ca –> stronger contraction

Question 33

Effect of B stimulation on SERCA pump?

Answer 33

• B stimulation –> turn on PKA [sympathetic path]
• get phosphorylation of phospholamban [PLB]
• removal of SERCA inhibition
• get more Ca uptake to SR by SERCA

Question 34

What is phospholamban?

Answer 34

• protein that inhibits SERCA

- when phosphorylated is inhibited so opens up SERCA for more Ca transport