Biomedical Engineering Reference
In-Depth Information
Phospholipase-C has generally a low activity in the heart. Four widespread PLC
isozymes exist (PLC
β
-PLC
). Isoform PLC
β
is activated by subunits of the Gq
subclass or by G
βγ
subunits of the Gi subclass members; PLC
γ
by receptor protein
by Ca
2
+
;PLC
Tyr kinases; PLC
δ
by the G12 subclass members.
5.5.3
Mitochondrial Calcium Uniporter
Mitochondrial Ca
2
+
uniporter contributes to Ca
2
+
signal shaping. In adult
cardiomyocytes, a fraction of mitochondria is apposed to terminal cisternae of
the sarcoplasmic reticulum, where ryanodine receptors are located to generate
Ca
2
+
-induced Ca
2
+
release. Hence, these mitochondria can transiently experience
high Ca
2
+
concentration during systolic, high-speed Ca
2
+
transients that can
overcome the relatively low affinity of mitochondrial Ca
2
+
uniporter for Ca
2
+
ion. In neonatal cardiomyocytes, the intramitochondrial Ca
2
+
level undergoes beat-
to-beat oscillations; the average peak magnitude in mitochondrial Ca
2
+
level is
quite small (
50% smaller than that in the cytoplasm [
393
]. At least in neonatal
cardiomyocytes, mitochondria significantly contribute to buffering the amplitude of
systolic cytosolic Ca
2
+
import [
393
]. Calcium peaks (20-30
∼
mol) are formed on
the outer mitochondrial membrane during systole; overexpression of mitochondrial
Ca
2
+
uniporter significantly reduces them.
5.5.4
Mechanotransduction
Mechanical stretch during diastolic filling triggers mechanotransduction that
regulates local production of reactive oxygen species. A small diastolic stretch
(8%) of a ventriculomyocyte indeed rapidly causes a burst of Ca
2
+
sparks
due to the release of free Ca
2
+
ions from intracellular stores. The microtubule
network links stretching to changes in concentration of reactive oxygen species and
intracellular free calcium ions. Cardiomyocyte stretching increases ROS production
by sarcolemmal NADPH oxidase NOx2 using the microtubule network that
then sensitizes nearby ryanodine receptors, thereby causing Ca
2
+
sparks [
394
].
68
NADPH oxidase NOx2 localizes to the junctional sarcoplasmic reticulum, thereby
allowing a rapid RyR2 oxidation and tuning RyR2 sensitivity to Ca
2
+
ion. Stretch-
dependent oxidation of RyR2 actually is a rapid and reversible control mechanism
68
Stretch-activated Ca
2
+
sparks are not influenced by stretch-activated channels, Ca
2
+
import,
Na
+
influx, nitric oxide signaling, and acute stretch-induced increases in sarcoplasmic reticulum
Ca
2
+
concentration. On the other hand, stretch-gated ryanodine receptors have an augmented Ca
2
+
sensitivity rapidly and reversibly in healthy cardiomyocytes when reactive oxygen and nitrogen
species react with their cysteine residues.
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