Cardiac Signaling Pathways and Vascular Signaling Pathways I

Question 1

Describe the mechanisms by which PKA-mediated phosphorylation of L-type Ca2+ channels affects inotropy and lusitropy

Answer 1

• L-type Ca2+ channels on the plasma membrane are activated by depolarization. Influx of Ca2+ through these channels triggers a larger Ca2+ release from the SR via RyRs (Ca2+-induced Ca2+ release—CICR).
• Sympathetic stimulation results in ↑cAMP and ↑PKA. PKA-mediated phosphorylation of L-type Ca2+ channels results in slowed inactivation. Thereby increasing the magnitude of the L-type Ca2+ channel induced influx of Ca2+ which results increases inotropy.

Question 2

Describe the mechanisms by which PKA-mediated phosphorylation of ryanodine receptors affects inotropy and lusitropy

Answer 2

Sympathetic stimulation also results in PKA-mediated phosphorylation of RyRs, increasing RyR sensitivity to Ca2+, so that less Ca2+ is needed to evoke Ca2+ release. This increases intropy

Question 3

Describe the mechanisms by which PKA-mediated phosphorylation of phospholamban affects inotropy and lusitropy

Answer 3

• PLB is an inhibitor of SERCA (which removes Ca2+ from cytosol following contraction and pumps it back into the SR).
• PKA-mediated phosphorylation of PLB results in PLB dissociation from SERCA, alleviating inhibition and increasing Ca2+ reuptake.
• Faster Ca2+ reuptake directly ↑luistropy (the ability of the heart to relax) and ↑inotropy by increasing SR Ca2+ load

Question 4

Describe the mechanisms by which PKA-mediated phosphorylation of troponin I affects inotropy and lusitropy

Answer 4

• TnI is the inhibitory unit of the troponin complex (TnC, TnI, TnT), which along with tropomyosin inhibits the actin-myosin interaction in the absence of Ca2+.
• Phosphorylation of TnI (TnI is phosphorylated by multiple kinases, including PKA) ↓Ca2+ sensitivity of TnC, which ↓inotropy; BUT also ↑ dissociation of Ca2+ from TnC, which ↑lusitropy—which allows the heart to fill more quickly, which is particularly important at higher heart rates

Question 5

Describe how HCN channels contribute to autonomic control of heart rate

Answer 5

HCNs produce the cardiac funny current (If), which is an inward (depolarizing current) at diastolic potentials.

Question 6

Describe how HCN channels contribute to sympathetic control of heart rate

Answer 6

Sympathetic stimulation of the SA-node cells causes an increase in cAMP. cAMP binds directly to HCNs, shifting the voltage dependence of activation, making the channels more likely to open, thereby providing more inward current to speed the rate of diastolic depolarization.

Question 7

Describe how HCN channels contribute to parasympathetic control of heart rate

Answer 7

• Parasympathetic stimulation via ACh activates M2 muscarinic ACh receptors, which are coupled to Gi/o. Activation of Gi/o releases two signals: the Gai/o subunit and the Gbg subunit complex.
• The Gai/o subunit inhibits adenylyl cyclase, ↓intracellular cAMP. This has the oppositve effect of sympathetic stimulation→↓cAMP binding to HCN and ↓ in inward current via HCN→slowing heart rate.

Question 8

Describe how L-type Ca2+ channels contribute to autonomic control of heart rate

Answer 8

• Action potentials in nodal cells are “slow” Ca2+ action potentials, thus changes in the magnitude and voltage-dependence of Ca2+ channels impacts the spontaneous firing rate.
• b-adrenergic stimulation increases L-type Ca2+ current and this effect is thought to contribute the sympathetic increase in heart rate

Question 9

Describe how L-type Ca2+ channels contribute to sympathetic control of heart rate

Answer 9

Sympathetic stimulation increases SR Ca2+ load via PKA-mediated phosphorylation of L-type Ca2+ channels and RyRs. ↑SR Ca2+ load in nodal cells→↑spontaneous release rate→contributes to the diastolic depolarization by activating inward current through the sodium-calcium exchanger (NCX)

Question 10

Describe how L-type Ca2+ channels contribute to parasympathetic control of heart rate

Answer 10

• Parasympathetic stimulation via ACh activates M2 muscarinic ACh receptors, which are coupled to Gi/o. Activation of Gi/o releases two signals: the Gai/o subunit and the Gbgsubunit complex.
• The Gai/o subunit inhibits adenylyl cyclase, ↓intracellular cAMP. This has the opposite effect of sympathetic stimulation→↓PKA mediated phosphorylation of L-type Ca2+ channels→↓SR Ca2+

Question 11

Describe how GIRK channels contribute to autonomic control of heart rate

Answer 11

• The Gbg subunit complex binds directly to GIRK channels to activate the IKACh current. IKACh is a K+ current, thus it hyperpolarizes the cell, driving the membrane potential toward the K+ equilibrium potential (away from the AP threshold), and slowing the spontaneous firing frequency.
• This is the primary mechanism for parasympathetic regulation of heart rate.