05: Excitation-Contraction Coupling Flashcards
1
Q
Why is the myocyte structure so complicated?
A
- Mature myocyte: 25 micrometers in diameter, 100 micrometers in length; 1-2 centrally located nuclei
- Each contains numerous myofibrils, which are long chains of sarcomeres (fundamental contractile unit).
- Sarcolemma surrounds the cell; T-tubules are invaginations of the sarcolemmal membrane
- Specialized region of membrane = intercalated disk; represents gap junctional complexes at interface of adjacent fibers (provide structural/electrical continuity)
- Ionized Ca2+ in EC fluid ~ 1mM.
- Ca2+ needed to saturate troponin C is 100-fold less.
- Large Ca2+ gradient: inability of diffusion to sufficiently and rapidly deliver Ca2+ to troponin C.
- Thus, most Ca2+ derived from internal stores in SR.
2
Q
Describe how T-tubules in myocytes function.
A
- T-tubules = extracellular space
- Allow Ca2+ trigger to be delivered deep within the myocyte
- Increase surface area of sarcolemma
- Sarcoplasmic reticulum (SR) abuts T-tubules at right angles in **lateral sacs (terminal cisternae) **–> intracellular Ca2+ stores
3
Q
How does the length of a sarcomere change during the cardiac cycle?
A
- Ventricular filling: 2.2 micrometers
- Contraction: 1.5 micrometers
NB: Measured from Z-line to Z-line
4
Q
What is the A-band?
A
Region of sarcomere occupied by thick filaments into which thin filaments extend from either side.
NB: Bands rotate polarized light (anisotropic)
5
Q
What is the I-band?
A
Region of sarcomere occupied only by thin filaments; extends to center of sarcomere.
NB: isotropic (lightly staining)
6
Q
What is the H-zone?
A
Area of thick filaments; no overlap with thin.
7
Q
What is the M-line?
A
Center of the A-band; thick filaments held together.
8
Q
What is the Z-disk structural lattice composed of, and what do its components do?
A
- Composed of actin, titin and nebulin, cross-linked by alpha-actinin.
- Disk serves as the anchoring plane of thin actin filaments and titin from opposing sarcomere halves.
- Titin keeps thick filaments centered in sarcomere during activation; molecular spring responsible for retractive force during stretch of relaxed muscle
- **Nebulin **helps align thin filaments in sarcomere
9
Q
What are the intermediate filaments of a sarcomere, and what are their functions?
A
- Composed of desmin, ankyrin and spectrins: form superstructure surrounding/supporting the sarcomere; attach the sarcomere to the sarcolemma at costamere.
- **Costamere **is a protein complex consisting of cytoskeleton, transmembrane glycoproteins and EC matrix; involved in trasnferring tension from contractile elements to connective tissue; common target of gene mutations resulting in dilated cardiomyopathy:
- **Dystrophin **(a costameric protein): absent in patients wtih Duchenne’s & Becker muscular dystrophy (X-linked dilated cardiomyopathy)
10
Q
What is myosin?
A
- Major protein of thick filaments; rigid tails woven into backbone; enzymatically active heads (ATPase activity) project as cross-bridges
- Contains 2 pairs of light chains associated with hinge regions
11
Q
What are thin filaments composed of?
A
- Actin, troponin and tropomyosin
- Monomeric form: G-actin
- Polymeric form: F-actin (basic structural unit of thin filament)
- Each 1/2 turn of F-actin contains 7 pairs of actin monomers
- Tropomyosin: regulates interactions between actin and myosin; one molecule for each of two grooves between 2 strands of actin
-
Troponin: made up of 3 proteins:
- Troponin I: Inhibits interaction between actin and myosin
- Troponin T: binds troponin complex to tropomyosin
- Troponin C: contains Ca2+ binding sites
12
Q
What factors affect myofilament Ca2+ sensitivity?
A
- Reduced by acidosis, **elevated phosphate and magnesium concentrations **(e.g., in ischemia) and beta-adrenergic activation
- Enhanced by caffeine and certain inotropic drugs
13
Q
Describe the stages of atrial and ventricular myocyte action potentials.
A
- Phase 0 (depolarization): impulse via gap junction causes voltage-gated Na+ channels to open –> rapid Na+ influx
- Phase 1 (early rapid repolarization): voltage-gated Na+ channels inactivated, voltage gated K+ channels open –> K+ efflux
- Phase 2 (plateau): L-type voltage-gated Ca2+ channels open, Ca2+ influx and K+ efflux –> plateau in electrical charge -> CONTRACTION
- Phase 3 (repolarization): voltage-gated slow K+ channels open, Ca-dependent Ca2+ channels inactivated (via calmodulin) –> massive K+ efflux
- Phase 4 (diastolic depolarization): Na/K+ pump maintains gradient
NB: Ventricle has longer plateau.
14
Q
What processes signal the heart to contract?
A
- Graded; depends upon Ca2+ and other factors
- Membrane depolarization activates L-type Ca2+ channel (Phase 2)
- Ca2+ enters cell through ICa (L type) and Na+-Ca2+ exchanger
-
ICa (L type)
- Ca2+-dependent inactivation: limits amount of Ca2+ entry through L-type during action potential (mediated by calmodulin bound to C-terminus of the channel)
- During E-C coupling, SR Ca2+ also contributes to inactivation (negative feedback on influx)
-
Na+-Ca2+ exchanger (NCX)
- Reversible; can transport Ca2+ into or out of cell
- Under physiologic conditions, NCX works mainly in Ca2+ extrusion mode
- Ca2+ influx increased greatly if intracellular Na+ elevated (i.e., digitalis), if SR Ca2+ release and/or L-type is inhibited or if action potential duration is prolonged.
-
ICa (L type)
- Ca2+ influx triggers SR Ca2+ release through ryanodine receptors (called Ca2+-induced Ca2+ release [CICR])
- High SR Ca2+ is basis for after-contractions, transient inward current and delayed after-polarizations that can trigger arrhythmias
15
Q
Describe the processes that regulate myocyte relaxation.
A
- Via SR Ca2+ ATPase (SERCA): ATPase that transfers Ca2+ from the cytosol of the cell to the lumen of the SR at the expense of ATP hydrolysis during muscle relaxation.
- Via sarcolemmal Na+-Ca2+ ATPase and Ca2+ ATPase
- Via mitochondrial Ca2+ uniport
20
Q
Describe cardiac glycoside modulation of cardiac contractility.
A
- Cardiac glyocsides (e.g., digoxin) are positive inotropic agents.
- Inhibit Na/K ATPase at the extracellular K+ binding site
- Less Na+ is pumped out of cell –> ↑IC Na+
- Gradient for Na+ decreased, leading to decreased Na+-Ca2+ pump
- ↑IC Ca2+ –> positive inotropic effect
