Cardiac & Vascular Signaling Pathways Flashcards
Describe the structure of GPCRs
7-transmembrane-spanning integral membrane proteins
List some types of GPCRs
Alpha & beta adrenergic receptors,
adenosine receptors,
glucagon receptors,
angiotensin receptors
Briefly describe GPCR’s activation
Agonist binds receptor->GTP replaces GDP on alpha subunit of heterotimeric G protein->dissociation of alpha & betagamma G protein subunits->Both alpha & betagamma can be active signals
Briefly describe GPCR’s deactivation
Auto dephosphorylation of GTP to GDP by alpha subunit->reassociation with betagamma. rebinding of G protein to receptor causes inactivation
What are the families of G protein involved in cardiovascular function?
Gs, Gi/o, Gq
Gs method of action
- stimulatory G protein
- activates adenylate cyclase
- Increases cAMP, activates PKA
- Heart: increase chronotropy, inotropy, lusitropy, dromotropy
- Skeletal muscle vascular beds: vasodilatation
Gi/o method of action
- inhibitory G protein
- inhibits adenylate cyclase
- Decreases cAMP, inhibits PKA
- Decreases chronotropy
Gq method of action
- activates PLC and PKC
- Increases Ca2+ (via IP3R activation & SR Ca2+ release)
- Vasoconstriction
Briefly describe PKA
Has 2 regulatory and 2 catalytic subunits. 4 cAMP units bind, releasing the catalytic subunits which can phosphaorylate target proteins
How does the sympathetic system regulate inotropy?
Symp. neurons innervate heart, release norepinephrine that binds to Beta adrenergic receptors, increasing intracellular cAMP, activating PKA. PKA acts on 4 different proteins:
- Phospholamban (PLB)
- L-type Ca2+ Channels (LTCCs)
- Ryanodine Receptors (RyRs)
- Troponin I (TnI)
What is the counterpart of PKA?
Phosphatases that dephosphorylates targets
Effects of PLB phosphorylation?
relieves inhibition of SERCA
faster Ca2+ reuptake into SR.
Increases lusitropy by increasing SR Ca2+ uptake
Increases inotropy by increasing SR Ca2+ load.
Effects of RyRs phosphorylation?
- Phosphorylation increases Ca2+ sensitivity, so that less Ca2+ is needed to evoke Ca2+ release
- Increases inotropy by increasing SR Ca2+ release.
Effects of TnI phosphorylation?
-TnI decreases Ca2+ sensitivity of troponin C
allows faster dissociation of Ca2+ so faster filling = increased lusitropy (not inotropy)
-Imp @ high HR
Parasympathetic regulation of inotropy
parasympathetic innervation of the ventricle is sparse, so little parasympathetic regulation of inotropy
Effects of LTCCs phosphorylation?
- Phosphorylation slows inactivation, increases entry of trigger Ca2+
- Increased Ca2+-induced Ca2+ release increases inotropy
What is the effect of blocking M2 muscarinic acetylcholine receptors w/atropine?
Increased HR by inhibiting tonic parasympathetic activity
What is the effect of blocking Beta adrenergic receptors with propanolol?
Decreased HR by inhibiting tonic sympathetic activity
T or F: under normal conditions, the parasympathetic tone at rest is less than the sympathetic tone
False, parasympathetic tone is greater at rest
What are the molecular targets for sympathetic regulation of chronotropy?
- HCNs
- LTCCs
- RyRs
- NCX
Sympathetic Regulation of Chronotropy: HCN
Activity increased by sympathetic stimulation via cAMP binding
Net inward (depolarizing) current = cardiac “funny current,”
Promotes excitability and spontaneous action potentials
Highly expressed in sinoatrial myocytes
Sympathetic Regulation of Chronotropy: LTCCs
Activity increased by sympathetic stimulation
Net inward (depolarizing) current
Promotes excitability and spontaneous action potentials
Sympathetic Regulation of Chronotropy: LTCC & RyRs
Increase HR
Sympathetic Regulation of Chronotropy: NCX
Promotes excitability and spontaneous action potentials
Intracellular Ca2+ is extruded by NCX, which generates a net inward current (2 Ca2+ out, 3 Na+ in)
Serves to remove Ca2+ from cytoplasm
How is Parasympathetic Regulation of Chronotropy mediated?
The release of acetylcholine from vagal nerve ending in the SA node, activates M2 muscarinic ACh receptors coupled to Gi/o heterotrimeric G protein which releases 2 signals: Galphai/o & Gbetagamma subunit complex
Targets of parasympathetic inhibition of chronotropy
- GIRKs (G-protein coupled inwardly-recitifying K+): Gbetagamma binds directly and stabilizes Vm near K+ Eq, dampening excitation: Primary mode
- HCN, LTCCs, RyRs (Galphai/o inhibits adenylyl cyclase): secondary mode
Characteristics of VSMCs
Small mononucleate cells
No sarcomeres = smooth, not striated
No troponin complex, no tropomyosin
Different contractile mechanism vs. striated muscle (Ca2+ release from SR not required)
Rate of contraction slower than striated muscle, but can be sustained
Triggers of smooth muscle contraction:
Contraction triggered by mechanical, chemical, or electrical stimuli (APs not required)
List the steps in VSMC activation
- Ca2+ enters cytoplasm from SR and/or plasma membrane Ca2+ channels
- Ca2+ binds to Calmodulin (CaM)
- Ca2+- CaM binds to Myosin Light Chain Kinase (MLCK), to activate it.
- Activated MLCK phosphorylates the myosin head – permits cross bridge cycling
- MLC dephosphorylated by Myosin Light Chain Phosphatase (MLCP), to halt contraction
Note: cAMP (via PKA) inhibits MLCK – causes VSMC relaxation
What are the 3 methods of vasculature control?
- Neural
- Intrinsic
- Humoral
What constitute neural control of vasculature?
Sympathetic regulation
Baroreceptor reflex
CNS control center
What is the result of sympathetic regulation of vasculature?
Vasoconstriction by direct activation of VSMC, INDEPENDENT of membrane depolarization
How does Sympathetic stimulation directly activates VSMC contraction ?
- Sympathetic terminals release NE – activates aARs on VSMCs (mainly a1 also some a2)
- aARs in VSMCs are coupled to Gq
- Gq activation causes IP3 production.
- IP3 increases cytosolic Ca2+ by activating SR Ca2+ release via IP3 receptors (similar to ryanodine receptors)
T or F: NE released by sympathetic neurons act on alpha1 receptors to cause vasoconstriction in all vascular beds
True, however Circulating epinephrine can activate b2ARs on VSMCs in skeletal muscle, causing vasodilation via cAMP/PKA inhibition of MLCK.
What are baroreceptors?
Pressure sensitive neurons found in in aortic arch and carotid sinus (High pressure); in atria and vena cavae (Low pressure)
What is the function of high pressure baroreceptors?
respond to increases in arterial pressure by increasing firing rate.
How are baroreceptors activated?
Stretch of arterial walls activates mechanosensitive eNac Na+ channels on baroreceptor cell membranes. Inward current causes depolarization, triggers APs in neurons
What is the Baroreceptor reflex?
SHORT TERM and rapid negative feedback mechanism for sudden changes in blood pressure (increase). The end result is a decrease in HR, decrease in inotropy, and decreased vascular tone by decreasing sympathetic tone and increasing parasympathetic tone output from cardiovascular center.
Where do the high pressure baroreceptors project?
Carotid sinus baroreceptors project to the “cardiovascular control center” in the medulla via glossopharyngeal nerve. Aortic arch baroreceptors project via the vagus nerve.
What mediated the “Bainbridge Reflex” ?
Low pressure baroreceptors
Describe vasculature control by vasoactive metabolites
-Vasoactive metabolites produced by metabolically active tissue = local feedback control of blood flow.
what is the PRIMARY MECHANISM TO MATCH BLOOD FLOW IN CAPILLARIES TO METABOLIC DEMAND?
Vasoactive metabolites (intrinsic control mechanism)
What are the vasoactive metabolites?
- decreased PO2
- increased PCO2 (decreased pH), partially due to lactic acid
- increased extracellular K+
- increased adenosine (byproduct of ATP hydrolysis): binds to A2 purinergic receptors on VSMCs. A2 receptors are GPCRs coupled to Gs = increased cAMP, vasodilation via inhibition of MLCK
What is the myogenic response?
- Feedback mechanism to maintain constant flow despite changes in pressure
- Increased pressure increases flow initially (Q = DP/R), but myogenic response counters by producing vasoconstriction to reduce flow.
T or F: Myogenic response can be overcome by vasoactive metabolites
True
How is the myogenic response mediated?
Stretch-activated ion channels of Trp family in VSMC membrane :
- non-selective cation channels, many isoforms
- inward current depolarizes cell, also direct Ca2+ entry
What are the 2 mechanisms of endothelial-mediated regulation?
- Nitric Oxide (NO) System
- Endothelin System
What is NO? Where is it produced?
A potent vasodilatation gas, produced by vascular endothelium vis nitric oxide synthase
-Labile, short half-life (10-60 s) = local effects
What is the function of NO?
-Basal NO release helps set resting vascular tone
-Nitric oxide is a major physiological mechanism for vasodilation.
Describe the action of NO in VSMC
- NO diffuses across membranes to VSMCs, where it activates guanylate cyclase to produce cGMP
- cGMP activates PKG
- PKG reduces intracellular Ca2+ via activation of SERCA, and inhibition of L-type Ca2+ channels
- Decreased Ca2+ causes vasodilation via reduced MLCK activity
What is Endothelin?
potent vasoconstrictor, produced by vascular endothelium, synthesized by Endothelin Converting Enzyme (ECE) and inhibited by NO & ANP
How does endothelin work?
- Endothelin released from vascular endothelium binds to ET receptors on VSMC (GPCRs coupled to Gq): vasoconstriction via IP3 and increased Ca2+
- Negative feedback via ET receptors on endothelial cells = NO production.
What is the natural counterpart to NO?
endothelin
What are the humoral systems of vasculature control?
Renin-Angiotensin-Aldosterone
Atrial Natriuretic Peptide
What is the Primary system for long-term control of blood pressure?
Renin-Angiotensin-Aldosterone System
What is Renin? function?
-Proteolytic enzyme released by renal juxtaglomerular cells
What promotes the release of Renin?
sympathetic stimulation, decreased blood pressure in renal artery, and decreased Na+ reabsorption
What is ANGIOTENSIN CONVERTING ENZYME (ACE)?
- Cleaves Angiotensin I into Angiotensin II, a vasoconstrictor
- ACE inhibitors & Angiotensin II receptor blockers = Therapeutics for treatment of hypertension & heart failure
Effects of Angiotensin II:
Direct effect = systemic vasoconstriction via binding to GPCRs on VSMCs.
Indirect effects: Stimulates sympathetic activity and release of aldosterone, endothelin, and ADH
What is aldosterone?
- Steroid hormone produced by the adrenal cortex
- Promotes reabsorption of Na+ and water in kidney collecting duct
- Increases blood volume and blood pressure
What is ADH?
ANTI-DIURETIC HORMONE (ADH, Arginine Vasopressin)
- Peptide hormone formed in hypothalamus, released by pituitary
- Increases water reabsorption in kidney
- Can also bind to receptors in vasculature to cause vasoconstriction.
What stimulates the release of ADH?
Release stimulated by hypovolemia, hypotension, high osomolarity, Angiotensin II, and sympathetic stimulation.
What is Atrial Natriuretic Peptide (ANP)?
- Vasodilator peptide released by atria (mostly right) in response to stretch
- Natriuretic = sodium excretion
What is the function of ANP?
-Long-term regulation of Na+ and water balance
-ANP increases glomerular filtration rate and secretion of Na+ and water (natriuresis and diuresis).
How does ANP function?
ANP binds to Natriuretic Peptide Receptors
Receptor guanylate cyclases (not GPCRs), produce cGMP
cGMP activates SERCA, stimulates Ca2+ uptake, decreases cytoplasmic Ca2+
What happens when someone stands up?
Blood pools in veins, decreased CO, decreased arterial pressure leads to activation of a compensatory reaction:
- Baroreceptor reflex: increased sympathetic tone. increased HR, CO, vasoconstriction.
- Myogenic Response: vasoconstriction due to increased pressure.
What are the main systems in Integrated Cardiovascular Response to Exercise?
- Central commend mechanism: Increased sympathetic and decreased para= increased CO, HR, inotropy, and increased arterial resistance in non-exercising muscles
- Local responses: vasodilatation due to vasoactive metabolites
How is there an increase in SV during exercise?
Activity of skeletal muscle increases venous return, Increase stroke volume via Starling’s Law
Acute blood loss results in what?
decreased mean arterial pressure (MAP), which results in decreased CO.
How does the body respond to acute blood loss?
- Baroreceptor reflex: Increased sympathetic tone due to decreased firing, also decreased para. resulting in increased HR and inotropy and vasoconstriction
- The renin-angiotensin system: activated by low BP, AII increases vascular tone, promotes ADH release to increase blood volume .
- Decreased capillary hydrostatic pressure: reabsorption from interstitial fluid, increasing blood volume.
What happens to max HR with Age?
decreases along w/ intrinsic HR
