06. Excitation-Contraction Coupling

• cardiac myocytes are striated muscle cells, but shorter than skeletal muscle.

  • branches are connected by intercalated discs
• intercalated discs contain desmosomes as a mechanical link and gap junctions as an electrical link

  • enables the heart to act as a mechanical and electrical syncytium
• sarcomeres are the basic contractile unit of a myocyte - containing both thick and thin filaments

  • thin = two stranded helix of actin monomers.
  • two tropomyosin monomers form a dimer and wrap around the actin - regulate binding to myosin
  • thick = two myosin heavy chains forming a helix - at the neck end there are two binding sites for actin
• there are two myosin light chains, one essential and one regulatory
• coordination between troponin complex, tropomyosin and actin allow for actin/myosin regulation via Ca2+ changes
• SAN generates electrical activity spontaneously, this spreads through the atrial tissue via gap junctions

  • slows through AVN
  • electrical activity spreads rapidly through ventricular tissue through gap junctions
• in cardiac myocytes, there is a plateau phase in the action potential

  • this is brought about by influx of calcium through L type calcium channels
  • balances out K+ efflux
• cardiac myocytes have deep invaginations called t-tubules, which make a continuum of the extracellular space

  • contain L-type Ca2+ channels
  • allow calcium to reach both deep and superficial regions of the myocytes
• the increase in Ca2+ due to L-type channels isn't enough to directly cause contraction, the signal is amplified by calcium induced calcium release (CICR)
• Ca2+ release channels of the sarcoplasmic reticulum are called RyRs, these have a mechanical link with L-type channels, so when the L-type channels open they cause the RyRs to open
• RyRs open for longer than L-type channels, so contribute more to calcium channels
• RyRs can be modulated by cytoplasmic Ca2+, PKA, and Ca2+ calmodulin dependent kinase II

  • as well as the link with L-type calcium channels
• increasing calcium levels leads to crossbridge cycling

  • cross bridges made between actin and myosin
  • calcium binding to troponin C causes conformational changes so tropomyosin moves out of the way
  • exposes myosin binding site

  ATP dependent
• calcium levels can fall due to:

  • removal of calcium across the cell membrane - Na+/Ca2+ exchanger NXC1 and Ca2+ ATPase PMCA - minor.
  • sequestering of calcium into sarcoplasmic reticulum - SERCA2a, which is regulated by phospholamban, when phosphorylated allows SERCA to sequester Ca2+ - major.
  • sequestering of calcium into the mitochondria - highly selective Ca2+ channels - minor.
• contraction AND relaxation both occur during the refractory period when Na+ channels are inactivated
• increasing intracellular calcium = increase in inotropy
• increasing opening of L-type Ca2+ channels:

  • adrenaline binds to beta 1 adrenoceptors on cardiac myocytes (GPCRs).
  • rise in intracellular cAMP.
  • increase in PKA activity - phosphorylates L-type calcium channels
  • increases their opening probabilities
• increasing opening of RyRs:

  • get phosphorylated due to circulating catecholamines py PKA
  • increase probability of being open
• inhibiting NXC1:

  • cardiac glycosides inhibit the sodium potassium pump
  • lead to increase in intracellular Na+
  • inhibits NXC1 leading to increase in intracellular Ca2+
• increasing sarcomere length increases Ca2+ sensitivity of the myofilaments

  • filaments are closer together, increasing probability of crossbridge formation
  • stretch activated calcium channels open, increasing influx of Ca2+
• increased rate of relaxation is called lusitropy
• as heart rate increases, the force of contraction increases - Bowditch effect
• increased heart rate causes increase in Ca2+ in sarcoplasmic reticulum as:

  • greater influx through L-type Ca2+ channels
  • at positive membrane potentials, NCX1 works in reverse.
  • stimulation of SERCA