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PHYSL 404 - Cardiovascular Physiology > Adrenergic Receptor Signalling > Flashcards

Adrenergic Receptor Signalling Flashcards

1
Q

What is cardiac reserve?

A

The potential ability of the heart to perform work beyond that necessary under basal conditions

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2
Q

How is Cardiac output calculated?

A

C.O.= SV x HR

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3
Q

What is the effect of sympathetic stimulation on cardiac contractibility?

A
  • Norepinephrine, epinephrine
    • Positive inotropy
      • Increases contractile force
    • Positive Chronotropy
      • Increases HR
      • faster contraction and relaxation will accommodate more beats/minute
    • Positive lusitropy
      • increases rate of relaxation
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4
Q

What is inotropy?

A

Changes in contractile force generation

Positive inotropic effect = increase in contractile force

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5
Q

Define chronotropy

A

Changes in HR by affecting the SA node

Positive chronotropic effect = increases HR

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6
Q

Define Lusitropy

A

Change in (rate of) relaxation

Positive lusitropy = increased rate of relaxation

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7
Q

Define dromotropy

A

Change in AV conductance

Dromotrophic = increased AV node conductance = Increased HR

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8
Q

What changes are collectively called “Cardiac Reserve”

A

Inotropy

Chronotropy

Lusitropy

Dromotropy

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9
Q

What is the structure of G-protein coupled receptor?

A
  • seven trans membrane segments
  • Intracellular C-terminus
  • Extracellular N-terminus
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10
Q

What are G-proteins?

A

Guanine nucleotide binding proteins

Heterotrimeric protein complexes comprised of Galpha, Gbeta and G gamma subunits

Four classes of G alpha subunits:

  • Galpha-s
  • Galpha i/o
  • G-alpha q/11
  • G-alpha 12/13
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11
Q

Which signaling pathway is triggered by the following G-protein alpha subunits?

  • Galpha-s
  • Galpha i/o
  • G-alpha q/11
  • G-alpha 12/13
A
  • Galpha-s
    • PKA
    • Gs -> Adenylyl cyclase -> cAMP -> PKA
  • Galpha i/o
    • Gi inhibits adenylyl cyclase
    • Go activates PLC which activates
      • IP3 to release Ca2+
      • DAG to release PKC
  • G-alpha q/11
    • Gq -> PLC which activates
      • IP3 to release Ca2+
      • DAG to release PKC
  • G-alpha 12/13
    • G? -> PLA2 -> AA
      • releases PKC and
      • Many AA metabolites
    • Gt -> PDE —> cGMP
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12
Q

Gi and Gs have opposing effects on ______

A

Gi and Gs have opposing effects on Adenylyl Cyclase

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13
Q

Draw a GPCR

A

Pay attention to localization of AC and PLC within the cell membrane

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14
Q

What are the 7 steps of GPCR signaling?

A
  1. Receptor activation
    • Ligand binding
  2. Conformation change of GPCR
  3. GDP is replaced with GTP on the alpha subunit
  4. Conformational change of G-protein
  5. Dissociation of GTP-bound G-alpha subunit from G beta gamma and from GPCR
    • dissociated Galpha-GTP goes on to activate the downstream effectors
  6. Hydrolysis of GTP to GDP on G-alpha (G-alpha has GTPase activity)
    • ligand comes off
  7. G-alpha reassociates with Gbeta-gamma ; G protein rebinds with receptor
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15
Q

How are the following adrenergic receptors distributed within the cardiovascular system?

Beta1-adrenoreceptors

Beta2-adrenoreceptors

Alpha-adrenoreceptors

A
  • Beta1-adrenoreceptors
    • Cardiomyocytes -> increase in contractility
    • SA nodes -> increase HR
  • Beta2-adrenoreceptors
    • SMC -> relaxation -> Vasodilation in the vasculature of skeletal muscles, bronchioles
  • Alpha-adrenoreceptors
    • SMC -> contraction

SMC = Smooth muscle cell

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16
Q

Which adrenergic receptor is dominant in the human heart?

A

Beta 1 adrenoreceptors

  • especially dense in SA nodal tissue
17
Q

Beta-1-AR (dominant AR in heart) is associated only with the ______ subunit to mediate which effects?

A

Beta-1-AR is associated only with the G-alpha-s subunit to mediate inotropic, chronotropic, lusitropic and dromotropic effects

Overall effect = increase heart performance

18
Q

Beta-2-AR activates _____ (subunit) to cause _______

Also associated with ______ to cause _______ in striated muscles

Minor contribution to increase in __________ (minor compared to beta1-ar)

A

Beta-2-AR activates Galpha-i (subunit) to cause relaxation of SMC and dilation of arterioles

Also associated with Galpha-s to cause increasing muscle contractility in striated muscles

Minor contribution to increase in cardiac output, contractility or HR (minor compared to beta1-ar)

19
Q

Alpha-1-AR

  • Activated by ____
  • Activates _____ subunit which activates _____
A

Alpha-1-AR

  • Activated by adrenaline
  • Activates G-alpha-q subunit which activates PLC
    • ​PLC cleaves PIP2 into IP3 and DAG
      • IP3 mediates release of Ca++ from ER/SR in SMCs triggering smooth muscle contraction
  • Vasoconstriction in many organs
  • contraction of uterus
20
Q

Which two signaling pathways can be activated by Beta-2-AR?

A

G-alpha-s and G-alpha-i

21
Q

How is activated beta-2-AR internalized?

A

Activated beta-2-AR can be phosphorylated (by PKA, PKC or GPCR-kinase (GRK)), coupled with arrestin and internalized (to be recycled back to the membrane or degraded)

22
Q

_______ decreases HR to normal sinus rhythm

A

Acetylcholine decreases HR to normal sinus rhythm

23
Q

Importance of Ach receptors in

  • SA node
  • AV node
  • Atrium
A

Importance of Ach receptors in

  • SA node
    • decrease heart rate to baseline sinus rhythm
  • AV node
    • reduct conduction velocity
  • Atrium
    • decrease atrial contration
24
Q

How can Ach inhibit an increase in HR?

A

By opposing activation of beta-AR

25
Q

Effect of cAMP on If

A

Increases HR by positively regulating If

26
Q

What catalyzes the conversion of ATP to cAMP?

A

Adenylate (adenylyl) cyclase (AC)

27
Q

What is the structure of Adenylate (adenylyl) cyclase (AC)?

A
  • two six-transmembrane domains
  • Two cytoplasmic catalytic domains (C1a and C2a)
28
Q

What is protein kinase A (PKA)?

A

cAMP-dependent protein kinase

  • Holoenzyme (apoenzyme + cofactor)
  • 2 regulatory subunits and 2 catalytic subunits
  • Phosphorylates its substrates
29
Q

What are phosphodiesterases (PDEs)?

A

A class of enzymes that degrade cyclic nucleotides (cAMP and cGMP)

30
Q

Of the 21 genes that encode PDEs, which 7 have been found in the heart

A
  1. PDE1
  2. PDE2
  3. PDE3
  4. PDE4
  5. PDE5
  6. PDE8
  7. PDE9
31
Q

What are phosphatases?

A

Phosphatases undo the function of kinases

ie phosphatases catalyze the dephosphorylation of proteins (at tyrosine or serine/threonine) or lipids

32
Q

What are the primary phosphatases coupled to GPCR

A
  • PP1
  • PP2A
  • PP2B (calcineurin)
33
Q

What are A-kinase anchor proteins (AKAPs)?

A
  • Provide a scaffold for the regulatory proteins such as kinases, PDEs and phosphatases
  • Work as a targeting device
    • bind to regulatory of PKA and confine the holoenzyme to discrete locations within the cell
  • Each AKAP contains a unique subcellular targeting domain that restricts its location within the cell
34
Q

Which AKAPs are located in the circulatory system and where are they located?

A
  • mAKAP
    • Cardiac myocytes
  • AKAP95
    • heart
  • AKAP148
    • heart
  • AKAP79
    • plasma membrane
35
Q

Which proteins are in the mAKAP complex?

A

mAKAP in cardiac myocytes has:

  • PKA
  • PDE4D3
  • protein phosphatase 2A
  • ERK5
  • EPAC1
36
Q

Describe the image

A
  • A) under basal condition: PKA is inactive and the PDE maintains low intracellular concentrations of cAMP
  • B) Upon hormonal stimulation, the generation of cAMP increases and overcomes the basal rate of PDE-mediated cAMP degradation -> PKA activation and phosphorylation of local substrates
  • PKA phosphorylation of mAKAP-anchored PDE enhances PDE activity
    • increases cAMP degradation and results in decreased PKA activity

PHYSL 404 - Cardiovascular Physiology (17 decks)

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