cardiac contractility

the excitation-contraction coupling (ECC) initiation

when an action potential excites the myocyte cell membrane (sarcolemma) along its transverse tubules

what does depolarisation after excitation cause

rapidly opens voltage-gated Na+ channels (Nav1.5) (stimulus) that further depolarize the cell membrane, allowing opening of voltage-gated Ca+ channels (Cav1.2) (trigger)

What triggers the opening of ryanodine receptor 2 channels

inward Ca2+. results in coordinated release of sarcoplasmic reticulum Ca2+ and Ca2+ induced Ca2+ release

what does the SR Ca2+ release contribute to

major portion of the myofilament-activating increase in Ca2+

what does Ca2+ SR bind to after release

troponin C of the troponin-tropomyosin complex on the actin filaments in sarcomeres, facilitating formation of cross-bridges between actin and myosin and myocardial contraction

conditions needed for relaxation

voltage-gated K+ channels open to allow an outward current that favours action potential repolarization. Ca2+ is taken back up into the SR through the action of the SR Ca2+ adenosine triphosphatase SERCA2a and is extruded from the cell by the sarcolemmal Na+ and Ca2+ exchanger

what is SERCA2a controlled by

phospholamban under resting conditions

ryanodine receptor isoforms

RYR1- skeletal muscles

RYR2- cardiac muscles

RYR3- brain and other tissues

what is RYR

a large homotetrameric protein complex with a large cytoplasmic N-terminus domain. An intracellular calcium release channel on the SR

what keeps the RYR2 channel closed

calstabin-2

what activates and inhibits RYR2

activated by low cytosolic Ca2+ 1-10micrometer and inhibited by high cytosolic Ca2+ 1-10mM

what inhibits RYR2

calmodulin in an independant manner

what increases RYR2 opening

phosphorylation sites for protein kinase A (pka) and for calmodulin dependent kinase II

where is calsequestrin-2

the low affinity and high capacity Ca2+ binding protein (binds 40-50 Ca2+) is in the SR lumen

what is calsequetrin 2

CASQ2 binds calcium ions, allowing the SR to store large amounts of calcium without precipitating, which is crucial for repeated cardiac contractions. Beyond buffering, CASQ2 modulates the ryanodine receptor 2 (RyR2) activity by forming a complex with RyR2, triadin, and junctin. This complex senses luminal SR calcium levels and adjusts RyR2 opening accordingly. At low SR calcium concentrations, CASQ2 inhibits RyR2 to prevent calcium release; at high concentrations, this inhibition is relieved, facilitating calcium release for muscle contraction.

summary of Ca2+ induced Ca2+ release

Ca2+ enter via a L-VACC.

Activation of cluster of RyRs

Local Ca2+ release- calcium spark

rapid summation of local events

global raise in Ca2+- calcium wave

contraction

how does caffeine affect RYR

at lower concentrations it increases RYR sensitvity to Ca2+ making it leaky. at 10mM it causes rapid calcium release.

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cardiac relaxation- mechanism of Ca2+ removal

• reuptake into the SR by SERCA (sarcoplasmic/endoplasmic reticulum calcium ATPase)

• extrusion by the Na+-Ca2+ exchanger

• uptake by mitochondrial Ca2+ uniporter

• extrusion by the sarcolemmal Ca2+ ATPase

slid 12

what inhibits SERCA (sarcoplasmic ER Ca2+ ATPase) pump

dephosphorylated phospholamban (PLB) binds to SERCA pump and inhibits its activity

what is SERCA

pumps Ca2+ from the cytosol back into the sarcoplasmic reticulum in muscle cells especially after contraction. uses ATP to actively transport Ca2+ against conc. gradient. allows muscle relaxation by lowering cytosolic Ca2+

how does caffeine affect RyR

increases its sensitivity to Ca2+ and at 10mM it causes rapid calcium release. reduces Ca++ content inside the SR. The force of contraction is determined by the amount of calcium available for release during systole (via CICR mechanism). If less calcium stored during relaxation the cardiac contractility is reduced.

what causes cytosolic calcium overload and trigger DAD leading to cardiac tachyarrythmia

drugs which make RyR leaky (excess caffeine and immunosuppressants), cardiac glycosides and genetics/acquired abnormal function in cardiac RyR2, CASQ2 and CaM

effect of PKA in SERCA

activated by cAMP in response to beta-adrenergic stimulation e.g adrenaline. phosphorylates PLN- SERCA can now enhance Ca2+ uptake in SR. faster relaxation

CaMKll in SERCA

activated by elevated intracellular Ca2+ levels. phosphorylates PLN. also acts on RyR2 increasing Ca2+ release from SR

NCX

Na+/Ca2+ exchanger which removes 20% of its cytosolic conc. driven by an increased in its conc. electrogenic- exchange 1 Ca2+ for 3 Na+

forward mode of NCX

repolarisation Phase 3. activated by increased cytosolic Ca2+. expels Ca for Na. can cause membrane depolarisation which triggers DADs in Ca2+ overload myocytes

Reverse mode NCX

depolarisation phase 0. activated by increased cytosolic Na+. expels 3 Na+ for 1 Ca2+

what is DAD

delayed afterdepolarization

catecholamines (adrenaline etc) inotropic effect

PKA phsphorylates L-type Ca2+ channels (increase in Ca2+ during depolarization), RyR on SR (increase Ca2+ release). Increase stroke volume and cardiac output.

catecholamines lusitropic effect

PKA phosphorylates PLN which removes PLN inhibition of SERCA (faster Ca2+ reuptake into SR) tropinin l phosphorylation reduces Ca2+ sensitivity of myofilaments

3 drug list other heart drugs

inhibition of Na+/K+ ATPase by binding to extracellular K+ binding site in a competitive manner. sodium build up. reverse NCX. more Ca- force of contraction increased

5 drug list other drugs

binds to TnC in Ca2+ dependent manner prolonging its active state.

5 benefits

doesn’t increase ATP consumption or cytosolic calcium. can synergise with PKA-dependent phosphorylation of tnl. inhibits PDE3a (increase cAMP). activates potassium ATP sensitive channels in blood vessels (vasodilation)

immunosuppressants

(like tacrolimus) bind Calstabin2 and makes the RyR-2 more leaky. increase cytosolic Ca++ concentration in cardiac myocytes. activates the NCX in the forward mode and, due to its electrogenic nature, lead to to membrane depolarisation. could trigger an additional action potential and premature excitation and contraction. If originated in atria this could lead to PSVT.

beta adrenoceptor agonists

All beta-adrenoceptor agonists will have positive inotropic effect (increasing L-VACCs, activity of RyR and sensitivity of myofilaments to Ca via PKA-mediated phosphorylation), positive chronotropic effect (enhancing HCN or if current directly by cAMP in pacemaker cells) and positive lusitropic effect (by increasing SERCA activity via PKA-dependent phosphorylation of phospholamban). Beta-agonists have little direct effect on calcium extrusion through the NCX.

beta-blockers reduce cardiac contractility

inhibits beta 1 adrenoceptors decreasing the activity of PKA and reducing calcium influx via the LVACC