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CVPR: CV Unit I > Cardiac Signaling Pathways > Flashcards

Cardiac Signaling Pathways Flashcards

1
Q

PKA phosphorylation of L-type Ca2+ channels effect on inotropy/lusitropy

A
  • Sympathetic stimulation results in ↑cAMP and ↑PKA.
  • PKA-mediated phosphorylation of L-type Ca2+ channels results in slowed inactivation.
  • slowed inactivation –> increased magnitude of the L-type Ca2+ channel induced influx of Ca2+ which results increases inotropy.
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2
Q

PKA phosphorylation of Ryanodine receptors (RyRs) effect on inotropy/lusitropy

A
  • PKA-mediated phosphorylation of RyRs –> increased RyR sensisitivyt to Ca2+
  • less Ca2+ is needed to evoke Ca2+ release –> increased intropy
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3
Q

PKA phosphorylation of phospholambin (PLB) effect on inotropy/lusitropy

A
  • PKA-mediated phosphorylation of PLB results in PLB dissociation from SERCA –> decreased inhibition of SERCA
  • decreased inhibition –> increased Ca2+ reuptake –> ↑luistropy (the ability of the heart to relax) and ↑inotropy by increasing SR Ca2+ load.
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4
Q

PKA phosphorylation of troponin I (TnI) effect on inotropy/lusitropy

A
  • TnI=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 (important at higher heart rates)
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5
Q

Phospholambin normal activity

A
  • PLB is an inhibitor of SERCA
  • SERCA removes Ca2+ from cytosol following contraction and pumps it back into the SR
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6
Q

Sympathetic stimulation of Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) effect on heart rate

A
  • HCNs produce the cardiac funny current (If) = “pacemaker current” (depolarizing current)
  • 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 –> more inward current to speed the rate of diastolic depolarization.
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7
Q

Parasympathetic stimulation of Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) effect on heart rate

A
  • ACh activates M2 muscarinic ACh receptors, which are coupled to Gi/o.
  • Activation of Gi/o –> Ga/i/osubunit and the Gbeta/gamma subunit complex.
  • Ga/i/osubunit inhibits adenylyl cyclase, ↓intracellular cAMP. This has the opposite effect of sympathetic stimulation.
  • ↓cAMP binding to HCN and ↓ in inward current via HCN→slowing heart rate.
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8
Q

Sympathetic stimulation of L-type Ca2+ channels effect on heart rate

A
  • b-adrenergic stimulation increases L-type Ca2+ current –> sympathetic increase in heart rate.
  • 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)
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9
Q

Parasympathetic stimulation of L-type Ca2+ channels effect on heart rate

A
  • ACh activates M2 muscarinic ACh receptors, which are coupled to Gi/o.
  • Activation of Gi/o –> Ga/i/o subunit and the Gbeta/gamma subunit complex.
  • Ga/i/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+ load in nodal cells→↓spontaneous release rate→slowing heart rate.
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10
Q

Stimulation of G-protein coupled inwardly-rectifying K+ (GIRK) channels effect on heart rate

A
  • The Gbeta/gamma 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.
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11
Q

Characteristics of Vascular smooth muscle cells (VSMCs) (6)

A
  • Small, mononucleated cells, which are electrically coupled via gap junctions.
  • Not striated, myofilaments are not arranged in the sarcomere.
  • Ca2+ release from the SR is not essential for contraction in VSMCs.
  • Rate of contraction is slower and contractions are sustained and tonic in VSMCs.
  • Contraction in VSMCs can be initiated by mechanical, electrical or chemical stimuli.
  • VSMCs do not have troponin.
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12
Q

Steps in Ca2+ regulation of vascular smooth muscle contraction (5)

A
  1. Ca2+ enters the cytoplasm from the SR (mainly) and from voltage-gated Ca2+ channels on the surface membrane.
  2. Ca2+ binds to calmodulin (CaM), a ubiquitous intracellular Ca2+ binding protein.
  3. Ca2+-CAM binds to myosin light chain kinase (MLCK), activating it.
  4. Activated MLCK phosphorylates the light chain of myosin (the myosin head), which permits cross bridge cycling to occur.
  5. Contraction halted by dephosphorylation of myosin light chain by myosin light chain phosphatase (MLCP).
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13
Q

cAMP effect on VSMCs vs. cardiac myocytes

A
  • @ cardiac myocytes = increases intropy/contraction
  • @ VSMCs = relaxation of cells
    • PKA-mediated phosphorylation & inhibition of MLCK –> reduced contraction
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14
Q

Sympathetic stimulation of vasculature mechanism

A
  • a1 adrenergic receptors = GPCRs coupled to the Gq G-protein.
  • Gaq activates phospholipase C (PLC)→DAG and IP3.
  • IP3 activates IP3Rs on SR of VSMCs.I
  • P3Rs are intracellular Ca2+ release channels. Activation of IP3Rs ↑Ca2+ release from the SR.
  • ↑Ca2+ →VSMC contraction and vasoconstriction.
  • PKC (a Ca2+ -dependent protein kinase) phosphorylates many targets in VSMCs, including L-type Ca2+ channels, which in turn activates additional intracellular Ca2+ release (CICR).
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15
Q

Arterial baroreceptors characteristics

A
  • pressure-sensitive neurons in the aortic arch and carotid sinus.
  • Mechanosensitive epithelial Na+ channels (eNaC) open in response to mechanical stimulation (stretching induced by high blood pressure) and the ensuing Na+ current depolarizes the baroreceptor neurons, causing them to fire action potentials.
  • Baroreceptor neurons project to a sensory area of the “cardiovascular control center” in the brainstem. Distinct output areas of the CV center control sympathetic and parasympathetic output to the heart and vasculature.
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16
Q

Arterial baroreceptor reflex arc

A
  • ↑blood pressure→↑baroreceptor firing rate→↓sympathetic output and ↑parasympathetic output from the cardiovascular center→↓heart rate, ↓inotropy and ↓vascular tone (vasodilation)→↓blood pressure.
  • The baroreceptor reflex is an acute short-term effect. Baroreceptors can adapt to prolonged changes in blood pressure by resetting to the new level over a time course of minutes to hours.
  • Sensitivity of the baroreceptor reflex ↓ in hypertension and aging, so there is less feedback response to changes in blood pressure.
17
Q

Types of vasoactive metabolites

A
  • ↓ PO2
  • ↑PCO2/pH
  • ↑K+: in active skeletal muscle, Na+ enters cell and K+ leaves during action potentials. With a high level of activity, the Na+/K+-ATPase can’t keep up, so K+ accumulates in interstitial space.
  • ↑Adenosine: Adenosine is used by hydrolysis of ATP. In VSMCs, adenosine binds to A2 purinergic receptors, which are GPCRs that are coupled to Gs. Thus, adenosine ↑cAMP levels in VSMCs causing vasodilation by inhibition of MLCK.
18
Q

Characteristics of myogenic response

A
  • The myogenic response is a feedback mechanism designed to maintain constant flow despite changes in pressure.
  • Mechanism is intrinsic to VSMCs—occurs in denervated vessels and is independent of vascular endothelium.
  • Stretch causes VSMC contraction by opening stretch-activated ion channels, which depolarize the VSMC, thereby ↑intracellular Ca2+ via L-type Ca2+ channels.
19
Q

Nitric oxide regulation of VSM tone

A
  • humoral regulators (ie ACh) stimulate activity of nitric oxide synthase (NOS) in vascular endothelial cells. Nitric oxide readily diffuses across the endothelial and vascular smooth muscle cell membranes. In VSMCs, NO activates guanylate cyclase→↑cGMP. cGMP activates PKG→↓intracellular Ca2+ via activation of SERCA and inhibition of L-type Ca2+ channels. ↓Ca2+ concentration causes relaxation of the VSMC (vasodilation).
  • NOS is highly susceptible to cardiovascular disease risk factors (oxidative stress, cigarette smoke)
  • Basal release of NO helps set resting vascular tone (↓NO→↑BP)
  • NO is anti-atherosclerotic and inhibits many steps in the development of plaques and ↓NO is associated with greatly increased risk for atherosclerosis.
  • Hypertensive patients often have ↓NO, which worsens there condition.
20
Q

Endothelin regulation of VSM tone

A
  • Endothelin is a potent vasoconstrictor produced by the vascular endothelium.Endothelin binds to ET receptors, GPCRs primarily coupled to Gq. Endothelin response is similar to the a-adrenergic response, but the time course is different.
  • Endothelin has both transient effects and longer lasting effects.
21
Q

Renin characteristics

A
  • released into circulation by the juxtoglomerular cells when stimulated by
  • (1) sympathetic stimulation of JG cells
  • (2) decreased blood pressure in the renal artery
  • (3) decreased sodium reabsorption in the kidney.
22
Q

Purpose of Renin-Angiotensin-Aldosterone system

A

kidney-mediated regulation of blood volume (and, indirectly, blood pressure)

23
Q

Mechanism of Renin-Angiotensin-Aldosterone system

A
  • Renin cleaves the circulating inactive protein angiotensinogen to angiotensin I (AI)—another inactive precursor.
  • AI is then cleaved by angiotensin converting enzyme (ACE) to form the active peptide, angiotensin II (AII)
  • Direct effects of AII: AII is a potent systemic vasoconstrictor which acts via binding to GPCRs on VSMCs.
  • Indirect effects of AII: (1) stimulates sympathetic activity→↑vasoconstriction; (2) ↑aldosterone release from adrenal cortex; (3) stimulates release of endothelin from vascular endothelium→↑vasoconstriction; and (4) stimulates release of ADH from the pituitary.
24
Q

Characteristics of aldosterone

A

promotes sodium and water reabsorption in the kidney→↑blood volume→↑blood pressure

25
Q

Characteristics of Anti-Diuretic Hormone (ADH)

A
  • formed in hypothalamus, released by pituitary.
  • ↑water reabsorption in the kidney
  • ↑peripheral vasoconstriction during systemic shock.
26
Q

Characteristics of Atrial natriuretic peptide (ANP)

A
  • Vasodilator peptide release by atria following mechanical stretch→endocrine function of the heart.
  • Involved in long-term sodium regulation and water balance, blood volume, and arterial pressure.ANP acts on ANPRs throughout the body. ANPRs are receptor guanylate cyclases (NOT GPCRs_ that produce cGMP, which activates SERCA to stimulate Ca2+ uptake.
    • Kidney: ↑glomerular filtration rate and ↑secretion of sodium and water.
    • Vasculature: ↑ vasodilation
    • Adrenal gland: inhibits release of aldosterone and renin release.

CVPR: CV Unit I (28 decks)

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