Regulation of CV system 1 Flashcards
Mechanism of Norepinephrine action of Beta1-adrenergic receptors in the heart
1) norepinephrine binds beta1 receptor (GPCR)
2) replace GDP by GTP on alpha subunit of G protein
3) alpha and beta-gamma subunits dissociate
4) alpha subunit –> activate AC
5) incr CaMP –> activate HCN PKA –> PKA phosphorylate
6) beta-gamma bind and activ Ca2+ or G inward rect K+ (GIRK)
7) Auto-dephos of GTP to GDP allows reassembly of G protein
What are targets of PKA-mediated phosphorylation?
1) L-type Ca2+ channels
2) RyR receptors
3) phospholamban
4) troponin 1
normal function of L-type Ca2+ channels
activ by depol
influx of Ca2+ that triggers further Ca2+ release from SR via RyR
Phosphorylation of L type Ca2+ channels causes…
Slows inactivation of L-type Ca2+ channels
increases magnitude of current
INCREASED INOTROPY
Phosphorylation of RyR causes
more sensitive to Ca2+
less Ca2+ needed to evoke Ca2+ release
INCREASES INOTROPY
Normal function of PLB
inhibits SERCA
inhibits removal Ca2+ from cytosol after contraction
Phosphorylation of PLB causes…
Dissociate from SERCA
increased Ca2+ reuptake after contraction
INCREASED INOTROPY AND INCREASED LUSITROPY (INCREASED SR CA2+ LOAD)
Normal function of troponin 1
inhibits actin-myosin interaction in absence of Ca2+
Phosphorylation of troponin 1 causes
decreases Ca2+ sensitivity of Troponin C/complex
increases rate of dissociation of Ca2+ from Troponin C
INCREASES LUSITROPY
Difference between Vascular smooth muscle cells and cardiac myocytes
striation
1) Smooth muscle = not striated (NO SARCOMERES)
Cardiac muscle = striated
Difference between Vascular smooth muscle cells and cardiac myocytes
TROPONIN
Smooth muscle = calcium dependent phosphorylation of myosin
Cardiac muscle = troponin on actin binds Ca2+ and initiates contraction
Difference between Vascular smooth muscle cells and cardiac myocytes
calcium role
Smooth muscle = does not require calcium release from SR
_____
Calcium reuptake similar in both smooth and cardiac muscle
Difference between Vascular smooth muscle cells and cardiac myocytes
rate of contraction
Smooth muscle = slower contraction
requires mechanical/electrical/chemical stim
Cardiac muscle = neuronal input then electrical stimulus
Difference between Vascular smooth muscle cells and cardiac myocytes
role of cAMP
Smooth muscle = cAMP causes relaxation
Cardiac muscle = cAMP causes contraction
Difference between Vascular smooth muscle cells and cardiac myocytes
nucleated/gap junctions
both are mononucleated with gap junctions
Steps in Ca2+ regulation of vascular smooth muscle contraction (THICK FILAMENT REGULATION)
- Ca2+ enters the cytoplasm from the SR (primarily) and plasma membrane channels
- Ca2+ binds Calmodulin (CaM)
- Ca2+-CaM binds Myosin Light Chain Kinase (MLCK)
- MLCK phosphorylates myosin head = myosin light chain = MLC to create cross-bridge
- Contraction stopped when the myosin head dephosphorylated by Myosin Light Chain Phosphatase (MLCP)
6) cAMP (via PKA) inhib MLCK –> relaxation
What is the effect of sympathetic stimulation on vascular tone?
Sympathetic innervation causes vasoconstriction INDEPENDENT OF MEMBRANE DEPOL
STeps in sympathetic regulation of smooth muscle contraction
- Norepinephrine binds a1-adrenergic receptor (some a2) on vascular smooth muscle cells
- Gq-alpha subunit of GPCR activ phospholipase C (PLC)
- PLC produces DAG and IP3
- IP3 activates IP3 receptors on the SR
- Activation of IP3 receptors causes Ca2+ release from L-type Ca2+ channels and the SR
- Increased intracellular Ca2+ levels cause contraction and vasoconstriction
What are the arterial baroreceptors?
Neurons in aortic arch and carotid sinus that increase firing rate in response to incr arterial pressure and stretch of arterial walls
Activation of basoreceptors causes…
SHORT TERM FOR SUDDEN CHANGE IN BLOOD PRESSURE
1) decr in sympathetic output
2) increase in parasympathetic output
DECREASE HR, INOTROPY
CAUSES VASODILATION
Steps of Baroreceptor reflex arc
- Epithelial Na+ channels (eNaC) open in response to stretching of the vessel walls
- Na+ current –> depolarization and AP is fired
- AP propagate down neuron to the cardiovascular control center (CV center) in medulla of brainstem
- CV center integrates signals from the neurons and regulates the sympathetic and parasympathetic responses
- Acute, short-term decrease in blood pressure
Gs
activ adenylate cyclase
incr cAMP
activ PKA
Gi/Go
inhib AC
decr cAMP
inhib PKA
Gq
activ PLC and PKC
incr Ca2+ via IP3R activ and SR Ca2+ release)
Structure of PKA
2 regulatory (each binds 2 cAMP) 2 catalytic units
binding of ___ causes dissociation of dissociation of regulatory and catalytic subunit of PKA
4 cAMP - 2 to each cAMP
HCN channels function
inward depolarizing current = funny current
Activity of HCN incr by ___
sympathetic stim via cAMP binding
HCN highly expressed where
SA myocytes for spontaneous AP
Primary mechanism for parasympathetic control of HR
Activation of IK ach current
- stabilize Vm near K+ equilibrium
- incr outward K+ current, decr excitability
Secondary mechanism of parasympathetic control of HR
inhibit inward current
hyperpol cell
decr excitability
Difference between Vascular smooth muscle cells and cardiac myocytes
smooth = phosphorylation causes relaxation by inhib MLCK
skeletal = phosphorylation causes incr force of contraction
What is the bainbridge reflex
low pressure baroreceptors in atria and vena cava incr HR in response to stretch
