Biomedical Engineering Reference
In-Depth Information
Ca
2
+
spike, but leaving a tonic Ca
2
+
flux until myocytes repolarize to
−
40 mV.
Rapid partial repolarization to 0 mV by the transient outward K
+
current (
i
K
,
to
)
through K
V
4 channels provokes a maximal Ca
2
+
spike (
∼
0.5 nA) [
328
]. The tonic
component of Ca
2
+
current via T tubules loads the sarcoplasmic reticulum with
Ca
2
+
ions.
Moreover, binding of Ca
2
+
to Na
+
-Ca
2
+
exchangers rapidly activates these
exchangers, thereby adding Ca
2
+
entry. Voltage-gated Ca
V
1.2 channels provoke
Ca
2
+
sparklets, RyRs cause Ca
2
+
sparks and waves. In fact, the transient Ca
2
+
entry
through sarcoplasmic reticulum ryanodine receptors yields the main Ca
2
+
input.
Adrenergic command modulate the magnitude and the dynamics of Ca
2
+
fluxes via
Ca
2
+
-calmodulin-dependent kinase CamK2 that targets all Ca
2
+
carriers.
Released Ca
2
+
ions (
10
3
ions/half-sarcomere) diffuse over a short distance
∼
×
15
10
3
mol/half-
sarcomere) of the troponin-tropomyosin complex on actin filaments [
328
]. Sub-
sequently, tropomyosin moves away from myosin-binding sites, thus enabling
actin-myosin cross-bridges (
∼
∼
×
(
1
m) to adjacent myofibrils and then bind to troponin-C (
25
10
3
/half-sarcomere) and converting the chem-
ical energy of ATP into force development (
∼
×
90
∼
2 pN/bridge for a maximal force
100 mN/mm
2
), hence allowing filament sliding and sarcomere shortening.
Synchronization of sarcomeres of normal left ventricle enables a fast pressure soar
and subsequent blood ejection.
Calcium release by the sarco(endo)plasmic reticulum during a heartbeat rises
the free cytosolic Ca
2
+
concentration from
∼
of
∼
∼
0.1 to
1
mol, above which the
∼
contractile response saturates (at
mol) [
328
]. Troponin-C has a binding site
for Ca
2
+
ion in this range of Ca
2
+
concentration. The Ca
2
+
-troponin-C mole-
cule enables sarcomere contraction by actin-myosin cross-bridges. At saturating
[Ca
2
+
]
i
, force increases with stretch over the range of sarcomere length at which
cardiomyocyte operates (1.5-2.3
2
m). At submaximal [Ca
2
+
]
i
, the sensitivity of
the contractile response depends on sarcomere length (length-dependent activation
[LDA]). Several mechanisms may contribute to LDA process. The first (minor)
mechanism supposes that sarcomere operates at constant volume, i.e., length
changes are associated with width (spacing between actin and myosin lattice)
changes, hence modulation of cross-bridge probability. Other mechanisms relies on
cooperativity between actin, troponin, and tropomyosin [
328
]: (1) Ca
2
+
-troponin-
C enhances binding of Ca
2
+
to neighboring troponin-C; (2) interaction between
troponin-tropomyosin units influences length-dependent effect of Ca
2
+
-troponin-C
activation; (3) cross-bridging improves binding of Ca
2
+
to adjacent troponin-C; and
(4) force exerted by cross-bridges on actin deforms this thin filament, hence actin-
troponin-tropomyosin complex, with enhanced binding of Ca
2
+
ion to troponin-C.
Released Ca
2
+
ions also rapidly reaches sarco(endo)plasmic Ca
2
+
AT P a s e
SERCA2 of the sarcoplasmic reticulum membrane that envelops the sarcomere.
Calcium ions are then sequestered back into the sarcoplasmic reticulum for efficient
lusitropy (myocardium relaxation). In addition, a moderate amount (
∼
30%) of
cytosolic Ca
2
+
is simultaneously extruded through NCX carriers, which enables
Na
+
entry.
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