Biomedical Engineering Reference
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of its Ca
2
+
sensitivity. However, in diseases, identical stretch creates transient
cytosolic accumulation of free Ca
2
+
ions that can propagate through the cell and
arrhythmogenic Ca
2
+
waves may result.
5.5.5
Sodium-Calcium Exchangers and Sodium-Potassium
Pumps
In cooperation with plasma membrane Ca
2
+
ATPase (PMCA), sarco(endo)plasmic
reticulum Ca
2
+
ATPase (SERCA), and Na
+
-K
+
-Ca
2
+
exchangers (SLC24a1-
SLC24a6), Na
+
-Ca
2
+
exchangers (NCX1-NCX3, or SLC8a1-SLC8a3) enable
recovery of intracellular calcium concentration to basal levels after stimulation.
Subtype NCX1 that exchanges 3 extracellular Na
+
for 1 intracellular Ca
2
+
is
ubiquitous. Both NCX2 and NCX3 are restricted to the brain and skeletal muscle.
However, NCX2 is also expressed in aortic and intestinal smooth muscles. On the
other hand, during cardiomyocyte depolarisation, Na
+
-Ca
2
+
exchanger can operate
in the reverse direction to allow calcium import and sodium export from the cytosol.
Na
+
-K
+
ATPase regulates cytosolic Na
+
concentration (main carrier for Na
+
extrusion in cardiomyocytes), hence Ca
2
+
level via Na
+
-Ca
2
+
exchanger. This
ATPase is composed of 2 subunits, a catalytic
α
subunit (NKA
α
1-NKA
α
4, or
AT P 1
α
1-ATP1
α
4) and a smaller glycoproteic
β
subunit (ATP1
β
1-ATP1
β
3). In
subunit isoforms of Na
+
-Ca
2
+
exchanger exist, NKA
the heart, different
α
α
1
is the dominant subtype, whereas NKA
α
2 and NKA
α
3 are present in smaller
amounts in human hearts [
395
]. Both NKA
α
1 and NKA
α
2 are connected to NCX in
cardiomyocytes. However, in mice,
α
2 subunit plays a greater role than
α
1 subunit
in modulating Ca
2
+
transients and cardiomyocyte contractility [
395
].
5.5.6
Normal and Impaired Calcium Signaling
Calcium sparks can be triggered by 3 mechanisms: (1) by opening of Ca
V
channels
in Ca
2
+
-release couplons during an action potential (Ca
2
+
-induced Ca
2
+
release
[CICR]); (2) by spontaneous openings of ryanodine receptors, especially when
sarcoplasmic reticulum Ca
2
+
load is high; and (3) by Ca
2
+
diffusion from nearby
Ca
2
+
-release couplons that have just liberated Ca
2
+
from the sarcoplasmic reticu-
lum, (spark-induced sparks), a minor process during normal excitation-contraction
coupling.
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