Excitation Contraction Coupling in Cardiomyocytes

Where does EC coupling occur

In Sarcolemma/T-tubules

Depolarization occurs down the sarcolemma

1. CaV1.2, Voltage gated L-type Ca2+ channels in the sarcolemma

2. Opens at around -35mV, allows for a small influx of Ca2_ from the EC space to IC space

3. 10-40% of Ca2+ comes from here

Calcium-Induced Calcium Release (CICR)

1. Ca2+ from EC space binds to Ryanodine Receptor type 2, RyR2 on the SR

2. Massive release of Ca2+ from the SR into the cytosol

3. 60-90% of Ca2+ for contraction is from here

Contraction

1. Ca2+ increase and binds to TnC on thin filament

2. Shift tropomyosin exposing myosin binding site on actin, forms a cross bridge formation creating a contraction

Relaxation Phase (Ca2+ Removal)

1. SERCA-2a (Sr Ca2+ ATPase)

   1. Pumps Ca2+ back into SR

   2. Works at about 80%

   3. Is regulated by Phospholamban which inhibit SERCA (when phosphorylated by PKA SERCA activity increases)

2. NCX (Na+/Ca2+ exchanger)

   1. 3 Na+ in, 1 Ca2+ out

   2. I_NCX current

3. Na+/K+ ATPase

   1. Maintain RMV

   2. 3 Na+ out, 2 K+ in

4. PMCA

   1. Plasma membrane Ca2+ ATPase

   2. Minor role

Skeletal Contractions

• Variable recruitment of muscle fibres controls contraction strength

  • CNS recruitment variable number of alpha motor neurons

• Frequency dependent, higher frequency of AP increase contraction

  • Summation, add AP to increase contraction and force

  • Tetanus, sustain muscle contraction

Cardiac Contractions

• 100% recruitment of myocytes occurs with every beat

• No tetany

  • Due to long AP duration, long plateau and refractory period

Strength of contraction modulated by

• Length-dependent mechanism

  • Contraction of each myocyte varies depending on the demand

  • Frank-starling law = increase EDV = increase force

  • Length-tension relationship = increase length = increase force

• Length-independent mechanisms (contractility changes)

  • Change in contractility (not related to sarcomere length)

    • Sympathetic and parasympathetic input

Frank Starling Law

More Blood returned to the heart, more EDV, longer sarcomere stretch, increase in Ca2+ sensitivity/increase in cross-bridge formation/increase in Ca2+ release = higher force production

Systolic Pressure is force +contractility (EDV +contractility)

• Adding positive inotropics will increase force for the same EDV

• Negative inotropics will decrease the force for the same EDV

Inotropy/inotropic

Force of contraction / change in force contraction

Chronotropy

Rate of heart beating

Dromotropy

• Rhythmicity of contraction

ionotropic

Action of Neurotransmitter that open/closes an ionic channel when it binds to its receptor

Positive Inotropics

• Noradrenaline

• Adrenaline

• Cocaine

• Amphetamines

• Digitalis (digoxin)

  • Drug after heart failure

Negative Inotropic

• Propranolol

• Nifedipine

• ACh

Sympathetic Regulation of EC

• Noradrenaline/norepinephrine binds to Beta 1 adrenergic receptor

  • Gs pathway

  • Gs activates AC, creates cAMP which binds directly to SAN HCN channels. cAMP also binds and activates PKA

Effects of Pka Phosphorylatin

1. Phosphorylate phophospolamban

2. Phosphorylate Cav1.2

3. Phosphorylate TnI

4. RyR2

Phosphorylation of Phospholamban

1. PLB will unbind from SERCA increasing activity

   1. Faster Ca2+ up, quicker relaxation (accommodate for faster HR)

   2. More Ca2+ available for contraction = increase contractility

2. PKA can also directly phosphorylate SERCA

3. Increase contractility/kinetics

Phosphorylation of Cav1.2

1. Increase the open probability of channels

2. Increase Ca2_ entry

3. More CICR

4. More Ca2+ released from SR

5. Higher force production/contractility

6. Increase contractility

Phosphorylation of TnI

1. Decreases affinity of TnC for Ca2+

2. Faster Ca2+ offloading

3. Promotes relaxation earlier to accommodate faster Hr

4. Force greater cause decrease affinity, let off calcium faster for SERCA to reuptake into SR

5. Increase in kinetics and contractility

Phosphorylation of RyR2

1. Increase fractional Ca2+ release from SR

2. Increase in contractility

Parasympathetic Regulation of EC

• Ach binds to M2 muscarinic receptor

  • Gi pathway

    • Inhibits AC, doesn't produce as much cAMP, doesn't activate PKA

Effects of Parasympathetic Regulation

• PLB remains on SERCA and inhibits

  • Longers Ca2+ reuptake, longer to relax, less Ca2+ release from SR

• Cav1.2

  • Decrease open probability, decrease Ca2+ entry, less Ca2+ release from SR, lower force production

• TnI

  • Higher Ca2+ affinity, longer offload time, longer to relax

• RyR2

  • Decrease in Ca2+ release from SR

Neural input on Sa Node vs Ventricular myocytes

• Both sympathetic and parasympathetic input

Ventricular myocardium

• In general it’s the presence/absence of sympathetic input that regulates contractility

  • Less M2 receptors than Beta 1

  • Para provides a modest break

Sympathomimetics

• Stimulate sympathetic NS

• Cocaine: blocks Norepinephrine reuptake by neurons

  • Increase time in synapse and time to interact with receptor

• amphetamines: release NE from storage vesicles

  • Increase activity in post synaptic neurons

Sympatholytic

• Inhibit the sympathetic NS

• Beta blockers

  • Propranolol

    • Used to arrythmia (atrial fibrillation)

    • Decrease Hr

    • Beta blockers refers to Beta 1 adrenergic

Digitalis (digoxin)

• Positive inotrope

• Inhibits NKA

  • Increase Na+ in the cytosol and causes NCX to run in reverse

    • Lower K+ in cytosol, depolarizes membrane potential and becomes more excitable

      • Closer to threshold

    • 3 Na+ out, Ca2+ in

      • Ca2+ in increase contractility