Regulation of cardiac output

Question 1

What are the steps for G-protein coupled receptor activation?

Answer 1

“1. Agonist binds receptor
2. Heterotrimeric G protein associates with receptor
3. GTP replaces GDP on α subunit of Gs
4. dissociation of α and βγ subunits from receptor
5. α subunit associates with and activates adenylate cyclase to stimulate cAMP production
6. βγ subunits bind to and activate Ca2+ channels or G-protein coupled inward rectifier K+ channels (GIRKs)
7. Auto-dephosphorylation of GTP to GDP allows reassembly of G protein complex
“

Question 2

What are the functions of Gs, Gi/o and Gq?

Answer 2

Gs (stimulatory G protein) activates adenylate cyclase which increases cAMP and activates PKA. Gi/o (inhibitory) inhibits adenylate cyclase which decreases cAMP and inhibits PKA. Gq activates PLC and PKC which increases intracellular Ca via IP3R activation and SR Ca release.

Question 3

For each receptor, list type of G protein and effect: alpha1 adrenergic, beta adrenergic, muscarinic Ach

Answer 3

α1 adrenergic is Gq and causes vasoconstriction. β adrenergic is Gs (beta 1 and 2) and cuases : increase chronotropy, inotropy, lusitropy, dromotropy in heart plus vasodilation in skeletal muscle vasculature. Muscarinic Ach receptor is Gi/o and decreases chronotropy.

Question 4

Mechanisms for sympathetic regulation of inotropy

Answer 4

Sympathetic NS causes NE release which binds to Beta adrenergic receptors, cAMP is increased, PKA is activated and phosphorylates Phospholamban, L-type Ca channels, Ryanodine receptors or Troponin I

Question 5

What is lusitropy?

Answer 5

ability of the heart to relax

Question 6

What is SERCA?

Answer 6

SERCA removes Ca2+ from cytosol following contraction (pumps it back into the sarcoplasmic reticulum (SR))

Question 7

How does phosphorylation of Phospholamban (PLB)by PKA affect inotropy and lusitropy?

Answer 7

PLB is an INHIBITOR of SERCA, and phosphorylation of PLB causes it to dissociate from SERCA, thereby relieving the inhibition and increasing Ca2+ reuptake rate into the SR. Increased SR Ca load increases inotropy. Also increases lusitropy

Question 8

How do L-type Ca channels work?

Answer 8

Depolarization activates LTCC’s and the influx of Ca through these channels triggers Ca release from SR via ryanodine receptors (Ca induced Ca release)

Question 9

How do L-type Ca channels affect inotropy and lusitropy?

Answer 9

Phosphorylation of LTCCs by PKA slows inactivation, thereby increasing the magnitude of the L-type Ca2+ current. This increase in “trigger Ca2+” elicits a larger release of Ca2+ from the SR, thereby increasing inotropy

Question 10

Explain Ryanodine receptors affect of inotropy and lusitropy

Answer 10

PKA also phosphorylates ryanodine receptors, making them more sensitive to Ca2+, so that less trigger Ca2+ is needed to evoke Ca2+ release

Question 11

How does Troponin I affect inotropy and lusitropy?

Answer 11

Phosphorylation of TnI by PKA decreases the Ca2+ sensitivity of TnC which results in faster dissociation of Ca2+ from TnC, thereby increasing lusitropy, which allows the heart to fill more quickly. It does NOT increase inotropy

Question 12

Parasympathetic regulation of inotropy?

Answer 12

None

Question 13

What is chronotropy?

Answer 13

Automaticity of heart

Question 14

What are the molecular targets for sympathetic stimulation of chronotropy?

Answer 14

a) Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs), b) L-type Ca2+ channels and ryanodine receptors, c) Ryanodine receptors and Sodium-Calcium exchanger

Question 15

What are the molecular targets for parasympathetic inhibition of chronotropy?

Answer 15

a) GIRKs, b) HCNs, L-type Ca2+ channels, and ryanodine receptors

Question 16

What do Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) do?

Answer 16

HCN channels produce the cardiac funny current (If), which is an inward (depolarizing) current at diastolic potentials. Found in SA node myocytes

Question 17

How does sympathetic stimulation of Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) affect chronotropy?

Answer 17

Sympathetic stimulation of SA cells causes an increase in cAMP which binds to HCN channels making the channels more likely to open, thereby providing more inward current to speed the rate of diastolic depolarization.

Question 18

How does sympathetic stimulation of L-type Ca channels/ryanodine receptors affect chronotropy?

Answer 18

β adrenergic stimulation increases L-type Ca2+ current and this effect is thought to contribute to the sympathetic increase in heart rate.

Question 19

How does sympathetic stimulation of ryanodine receptors and Na/Ca exchanger affect chronotropy?

Answer 19

The increased SR Ca2+ load in nodal cells increases the spontaneous Ca2+ release rate, and contributes to the diastolic depolarization by activating inward current through the sodium-calcium exchanger (NCX)

Question 20

Parasympathetic regulation of pacemaking is mediated by what?

Answer 20

Release of acetylcholine (ACh) from vagal nerve endings in the sinoatrial node. ACh activates M2 muscarinic ACh receptors, which are coupled to the Gi/o heterotrimeric G protein. Activation of Gi/o releases two signals: the Gαi/o subunit and the Gβγ subunit complex.

Question 21

How does parasympathetic inhibition of GIRK affect chronotropy?

Answer 21

The Gβγ subunit complex binds to GIRK channels to activate the IKACh current. IKACh stabilizes the membrane potential near the K+ equilibrium potential, thereby dampening excitation and slowing the spontaneous firing frequency

Question 22

How does parasympathetic inhibition of HCN, LTCC and ryanodine receptors affect chronotropy?

Answer 22

The Gαi/o subunit inhibits adenylate cyclase, thus reducing intracellular cAMP levels. This has the opposite effect to sympathetic stimulation of pacemaking

Question 23

What is the primary mechanism for parasympathetic control of HR?

Answer 23

IKAch