CV Week 1b Flashcards
What is the primary mechanism of EC coupling? What are the 3 main steps?
CALCIUM cytosolic fluctuations
1) Ca2+ enters cell via DHPR (L-type Ca2+ channel) → activates RyR2 in SR → flux of Ca2+ into myoplasm
2) Ca2+ binds troponin → myosin binds actin → contraction
3) Ca2+ removed from myoplasm by → relaxation
3 mechanisms by which Ca2+ is removed from the cytoplasm
In order of most contribution:
1) SERCA2 pump
2) NCX Na+/Ca2+ exchanger
3) ATP Ca2+ pump (PMCA) - minimal contribution
SERCA2 pump
- pumps Ca2+ into SR, on longitudinal SR
- Ca2+ binds calsequestrin (low affinity, high capacity) in SR
- Dominant mechanism of removal of Ca2+ because longitudinal SR surrounds each myofibril (requires less energy)
- Inhibited by PLB
NCX located in _________
junctional domains of plasma membrane and t-tubules
______ muscle REQUIRES entry of external Ca2+ where as _______ muscle does not
Cardiac
Skeletal
Explain the bidirectional qualities of NCX
3 Na for 1 Ca
At beginning of AP (phase 0) Na+ out/Ca2+ in (depolarization)
At end of AP (phase 3/4) Na+ in/Ca2+out (repolarization, steady-state)
Maintains balance of Ca2+ entry during steady-state
How is NCX arrhythmogenic?
If Ca2+ released from SR when cardiac myocyte at REST (diastole) → causes 3Na+ in/1Ca2+ out → depolarization
→ delayed afterdepolarizations and arrhythmias
2 mechanisms of calcium homeostasis
1) NCX exchanger
2) L-type Ca2+ channel and CDI
Calcium Dependent inactivation (CDI)
-L-type Ca2+ channel undergoes inactivation dependent on [Ca2+] near cytoplasmic side of channel
-maintains constant SR Ca2+ content
If amount of Ca2+ in SR increases, greater CDI causes less Ca2+ to enter via L-type channel.
-If amount of Ca2+ in SR decreases, less CDI causes more Ca2+ to enter via L-type channel.
Sympathetic Activation → (4)
1) Positive Lusitropy: increase rate of relaxation
2) Positive Inotropy: increase contractile force
3) Positive Chronotropy: increased HR by raising pacemaker firing rate in SA node
4) Alter propagation through conduction pathways
Targets of PKA
1) L-type Ca2+ channel
2) RyR2
3) Phosphoalmban (PLB)
4) Troponin
PKA effect on L-type Ca2+ channel
Phosphorylation → increases amplitude of L-type Ca2+ current → increases size of RyR2 activation
Increase Ca2+ entry → increase quantity of Ca2+ stored in SR
→ Contributes to POSITIVE INOTROPY
PKA effect on RyR2 channel
phosphorylation of RyR2 → Ryr sensitized to activation by Ca2+
→ POSITIVE INOTROPY
PKA effect on PLB
- Association of PLB with SERCA2 inhibits Ca2+ pumping activity
- Phosphorylation → PLB dissociates from SERCA2 → relieves inhibition and increases Ca2+ pumping into SR
→ Speeds relaxation, increases the quantity of Ca2+ stored in SR
→ Both POSITIVE INOTROPY and POSITIVE LUSITROPY
PKA effect on Troponin
phosphorylation → speed rate of Ca2+ dissociation from actin
→ POSITIVE LUSITROPY
Timothy Syndrome
Other associated abnormalities?
Associated mutations?
Impact of mutations?
Outcomes?
syncope, cardiac arrhythmias, sudden death
Associated with intermittent hypoglycemia, immune deficiency, and cognitive abnormalities (autism)
De novo mutations in Cav1.2 (L-type Ca2+ channel)
→ profound suppression of voltage-dependent inactivation of Ca2+ channel → prolonged AP
→ AV block, prolonged QT intervals, polymorphic ventricular tachycardia
Brugada syndrome (aka sudden unexplained death syndrome)
Associated with a number of ECG alterations (revealed by administration of Class IC antiarrhythmics - Na+ channel blockers)
Mutation in cardiac Na+ channel (Nav 1.5), Transiently outward K+ channel, and L-type Ca2+ channel
→ large reduction in magnitude of L-type Ca2+ current as consequence of impaired membrane trafficking current
→ shortened AP
→ Significantly shortened Q-T intervals.
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
No ECG abnormalities at rest, but abnormalities with exercise or infusion of catecholamines
Mutations in RyR2 (AD inheritance)
Mutation in calsequestrin 2 (CasQ2) (AR inheritance)
CPVT mutations + increased SR Ca2+ release (due to increased ___________) → ?
increased B-adrenergic receptor activation
–> Ca2+ release NOT directly triggered by L-Ca2+ current during AP plateau
–> Ca2+ release occurs after repolarization
Extrusion of Ca2+ via NCX → depolarizations that can trigger ectopic APs and initiate arrhythmias
Treatment of CPVT
B-blockers are not effective
- Must block aberrant Ca2+ release from RyR2
- Flecainide (class IC antiarrhythmic) possible therapy
Mutations in RyR2 in CPVT causes…
Increase resting “leak” of Ca2+ out of SR and/or render RyR2 more sensitive to activation by Ca2+
Mutations in calsequestrin2 (CasQ2) in CPVT causes…
Homozygous CasQ2 mutations → dramatic loss of luminal Ca2+ buffering, some result in no effect.
CasQ2 has role in regulation of RyR2 function
-This regulation may be altered in CPVT CasQ2 mutations
cAMP dependent protein kinase
PKA
G protein associated with alpha 1 adrenergic receptor
Gq
Signaling pathway associated with alpha 1 adrenergic receptor activation
PLC, PKC-> increase intracellular Ca2+
Effect of alpha 1 adrenergic receptor activation
vasoconstriction
G protein associated with beta adrenergic receptor
Gs
Signaling pathway associated with beta adrenergic receptor activation
stimulates adenylate cyclase, increases cAMP, PKA activation
Effect of beta adrenergic receptor activation
heart: increase chronotropy, luisotropy, inotropy, dromotropy
G protein associated with muscarinic Ach receptor
Gi/o
Signaling pathway associated with muscarinic Ach receptor activation
inhibits adenylate cyclase, decreases cAMP
- releases beta gamma subunits
Effect of muscarinic Ach receptor activation
Decrease chronotropy
Channels that produce If (funny current)
Hyperpolarization-Activated Cyclic Nucleotide-Gated channels (HCNs)
Sympathetic stimulation to SA node cells → increase cAMP → cAMP binds HCN channels → ?
make channels easier to open (shift voltage dependence activation)
→ speeds rate of diastolic depolarization
B-adrenergic (sympathetic) stimulation → increased L-type Ca2+ current →
Increase heart rate
Sympathetic stimulation → increased SR Ca2+ load via PKA phosphorylation via LTCC, RyR, and PLB→
increase spontaneous Ca2+ release rate → more diastolic depolarization by activating inward current through sodium-calcium exchanger (NCX) → faster firing rate
Molecular targets for sympathetic control of chronotropy (3)
- Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels (HCNs)
- L-Type Ca2+ channels and RyR
- RyR and Sodium-Calcium Exchanger (NCX)
Parasympathetic control of chronotropy occurs through activation of _____ receptors by _____
M2 muscarinic receptors
Ach
M2 receptors coupled to ____ G protein → activation → ____ and ___ subunits released as signals →
Gi/o
Gai/0 and GBy
inhibit AC → reduce cAMP
Molecular targets for parasympathetic inhibition of chronotropy
- GIRKs
2. HCNs, L-type Ca2+ channels, and ryanodine receptors
G-Protein Coupled Inwardly Rectifying K+ (GIRKs)
GBy subunit → binds GIRK channel → increase K+ current in → stabilize membrane potential near Ek → dampens excitation, slows firing frequency
Parasympathetic effect on HCNs, LTCC, and RyR
Gai/o subunit → inhibit adenylate cyclase → reduce cAMP levels → Reduce inward current via HCN channel, LTCC, and RyR-NCX
6 properties of vascular smooth muscle cells (VSMCs) that differentiate them from cardiac myocytes
i. Small, mononucleated cells, electrically coupled via gap junctions
ii. Not striated, NO SARCOMERES
iii. NO TROPONIN OR TROPOMYOSIN
iv. Ca2+ release from SR not essential for contraction in VSMCs
- Ca2+ regulation of smooth muscle contraction via myosin
v. Rate of contraction slower and contractions are sustained and tonic in VSMCs
vi. DIFFERENT CONTRACTILE MECHANISM: Contraction initiated by mechanical, electrical or chemical stimuli
3 types of contractile mechanisms in VSMCs
- Mechanical stretching → contraction via myogenic response
- Electrical depolarization → contraction via LTCC activation (graded potential sufficient, AP not required)
- Chemical stimuli (neuronal/hormonal regulators) → directly activate contraction
Ca2+ regulation of VSM contraction (5)
- Ca2+ enters cytoplasm from SR (mainly) and voltage-gated Ca2+ channels on surface membrane
2) Ca2+ binds to calmodulin (CaM), intracellular Ca2+ binding protein
3) Ca2+-CAM binds to myosin light chain kinase (MLCK), activating it
4) Activated MLCK phosphorylates light chain of myosin (myosin head), → permits cross bridge cycling to occur
5) Contraction halted by dephosphorylation of myosin light chain by myosin light chain phosphatase (MLCP)
cAMP causes _____ of VSMCs via:
relaxation
via inhibition of MLCK
Autonomic regulation of vasculature is primarily ___
sympathetic
leading to vasoconstriction
Sympathetic stimulation in VSMCs occurs through ____ receptors
alpha 1 adrenergic
A1 adrenergic receptors
GPCRs coupled to Gq G protein
→ Ga1 subunit → activates PLC → produces DAG and IP3
IP3 → activates IP3 receptors on SR of VSMCs → IP3R channel releases Ca2+ into cytoplasm from SR → VSMC contraction
PKC furthers VSMC contraction by activating inward current via LTCCs → CICR
Sympathetic innervation of vascular beds _____ in skin and kidneys but ____ in cerebral and coronary circulations
abundant
sparse
Arterial baroreceptor reflex
acute, short-term neural mechanism for control of BP
i. Pressure-sensitive NEURONS in aortic arch and carotid sinus.
1. Adapt to prolonged changes in BP
2. Sensitivity ↓ in hypertension and aging
Baroreceptors respond to stretch in arterial walls by
Increasing firing RATE
1.MECHANOsensitive epithelial Na+ channels (eNaC) open in response to stretch induced by high BP → Na+ current depolarizes baroreceptor neurons → fire APs
Baroreceptor neurons fire APs that project into the ____
“Cardiovascular Control Center”
- CV control center integrates signals from baroreceptors and other brain brain regions
- Output projections of sympathetic and parasympathetic fibers to heart and sympathetic fibers to vasculature
Arterial baroreceptor reflex arc:
↑BP→↑baroreceptor firing rate
→ CV control center → ↓sympathetic output and ↑parasympathetic output from CV center
- → ↓heart rate, ↓inotropy and ↓vascular tone (vasodilation)
- → ↓blood pressure
Primary mechanism of blood flow matched to metabolic demand of tissue
Vasoactive metabolites
Vasoactive metabolites (4)
all act to cause vasodilation
- ↓ PO2
- ↑PCO2/pH
- ↑ extracellular K+: in active skeletal muscle, Na+ enters cell and K+ leaves during APs
a. High level of activity → Na+/K+-ATPase can’t keep up → K+ accumulates in interstitial space - ↑Adenosine: produced by hydrolysis of ATP
a. In VSMCs, binds A2 purinergic receptors (GPCR) coupled to Gs
b. ↑ Adenosine = ↑cAMP levels in VSMCs → vasodilation by inhibition of MLCK
Myogenic response
Feedback mechanism that maintains constant flow despite changes in pressure
1.Independent of metabolic demand
EX) postural change
Mechanism of myogenic response
Intrinsic to VSMCs - occurs in denervated vessels
Stretch → open stretch-activated Trp ion channels → inward Ca2+ current → VMSC contraction → vasoconstriction and depolarization of VSMC → further increase in intracellular Ca2+ via LTCC
Myogenic response can be overcome by vasoactive metabolites
Nitric oxide (NO) regulation of VSM tone
VASODILATOR produced in vascular endothelium by nitric oxide synthase
- Short half life → local response
- Basal release of NO sets resting vascular tone (↓ NO = ↑ increase BP)
- Agonist stimulated release = MAJOR mechanism for vasodilation
NO and disease: (4)
- Susceptible to CV disease risk factors (smoking, oxidative stress, etc.)
- NO is anti-atherosclerotic, inhibits development of plaques
- ↓NO is associated with greatly increased risk for atherosclerosis
- Pts with HTN often have ↓NO, which worsens their condition
NO pathway
i. Vascular endothelial cells → produce NO via NO synthase (NOS)
- Humoral regulators (ACh, bradykinin) stimulates activity of NOS
ii.VSM cells → site of NO action
iii. NO → activate guanylate cyclase → produce cGMP → cGMP activate Protein Kinase G (PKG)
→ reduce intracellular Ca2+ via activation of SERCA and inhibition of LTCC
→ Relaxation of VSMC → vasodilation
Endothelin regulation of VSM tone
i. VASOCONSTRICTOR produced by vascular endothelium with Endothelin Converting Enzyme (ECE)
- Endothelin binds ET receptors (GPCRs on VSMCs)
- ET receptors coupled to Gq → increase intracellular Ca2+ in VSMC → Vasoconstriction
ii.Has both a transient (a-adrenergic effect) and a longer lasting effect
Primary system for long term control of BP
Renin-angiotensin-aldosterone system
Renin
proteolytic enzyme released by juxtaglomerular (JG) cells in renal glomerulus
Renin release stimulated by (3)
1) Sympathetic stimulation of JG cells
2) Decreased BP in renal artery
3) Decreased Na+ resorption in kidney
What does renin do?
Cleaves circulating inactive protein angiotensinogen → angiotensin I
Angiotensin I cleaved by Angiotensin Converting Enzyme (ACE) to Angiotensin II
Angiotensin II (5)
ACTIVE FORM, potent vasoconstrictor
- Systemic vasoconstriction via binding to GPCRs on VSMCs
- Stimulates sympathetic activity (thus more vasoconstriction)
- Stimulates aldosterone release from adrenal cortex
- Stimulates release of endothelin from vascular endothelium
- Stimulates release of ADH from pituitary
Aldosterone
produced in adrenal cortex
i. Hormone, acts on receptors in kidney collecting ducts
ii. Promotes resorption of Na+ and water → increase blood volume → increase BP