Lec 9 Cellular Regulation Flashcards
What is I[K,Ach]?
Acetylcholine-sensitive K current
What is HCN?
Hyperpolarization-activated, cyclic nucleotide-gated
- another name for funny current
What is positive chronotropy?
faster heart rate
What is positive inotropy?
stronger contraction
What is positive dromotropy?
faster cell to cell conduction
What is positive lusitropy?
faster relaxation
How does parasympathetic stimulation affect HR?
decrease HR
How does parasympathetic inhibition affect HR?
increase HR
What does propanolol do?
B-adrenergic receptor blocker
thus inhibits sympathetic
What does atropine do?
Muscarinic Acetylcholine receptor blocker
thus inhibits parasympathetic
Does parasympathetic or sympathetic inhibition have a bigger effect on HR?
- parasympathetic inhibition has a much stronger effect [increases HR by a lot]
- sympathetic inhibition decreases HR but not by as much
Is resting HR dominated by sympathetic or parasympathetic?
parasympathetic
What are two consequence of parasympathetic tone of HR?
- inhibition of parasympathetic has greater effect than inhibition of sympathetic
- stimulation of sympathetic has greater effect than stimulation of parasympathetic
What is the difference in time course between parasympathetic and sympathetic stimulation?
- parasympathetic stimulation is faster and goes away faster
What kind of cholinergic receptors are in SA and AV node? What important kind are missing?
- Muscarinic Ach receptors present
- Nicotinic Ach receptors absent
How is parasympathetic effect mediated [pathway of action]? What secondary messenger involved?
- ACh released from nerve into synaptic cleft
- ACh binds G-protein coupled muscarinic receptor
- GPCR inhibits adenylyl cyclase [AC] so get decrease in cAMP, decrease protein kinase A [PKA]
What innervates ventricular muscle?
sympathetics ONLY
What is effect of G-beta-gamma subunit in SA node?
- dissociates from M receptor at activation
- binds and open acetylcholine-sensitive K current [I(K,ACh)]
- cAMP independent effect
What activates I(K,Ach)?
G-b-gamma subunit of GPCR that dissociated from M receptor in presence ACh
What type of current is Ikach?
- 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
What is affect of parasympathetic stimulation on AV node?
- decrease in PKA activity
- slower conductance [negative dromotropy]
Where in heart are parasympathetic effects vs sympathetic effects acting in heart?
parasympathetic: SA, AV, atria
sympathetic: SA, AV, ventricle
What is effect of sympathetic stimulation [pathway]?
- via Epi/NE
- activates Gs coupled B adrenergic receptors
- activates adenylate cyclase –> activated cAMP –> more Protein kinase
What is sympathetic effect on funny current? How?
- sympathetic stimulation activates funny current directly via cAMP
- funny current = depolarizing Na current so increasing it increases speed of SA node firing
Does funny current activation by cAMP require phosphorylation?
No - no phosphorylation or PKA involved, just direct effect from cAMP
How does increased funny current increase HR?
less time required to depolarize membrane
How does sympathetic affect AV?
- increased AV
- positive dromotropy [faster conduction]
What mech explain why SA node effect by parasympathetic is faster than sympathetic?
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
What 2 effects does sympathetic stimulation have on ventricle?
- positive inotropy [stronger contraction]
- positive lusitropy [faster relaxation]
What is isoproterenol?
B-adrenergic agonist
stimulates sympathetic
What are 4 downstream targets of B-adrenergic stimulation in ventricle?
- L-type Ca channel
- phospholamban
- RyR
- Troponin I
Effect of B stimulation on L-type Ca current?
- 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
Effect of B stimulation on SERCA pump?
- B stimulation –> turn on PKA [sympathetic path]
- get phosphorylation of phospholamban [PLB]
- removal of SERCA inhibition
- get more Ca uptake to SR by SERCA
What is phospholamban?
- protein that inhibits SERCA
- when phosphorylated is inhibited so opens up SERCA for more Ca transport
