Biomedical Engineering Reference
In-Depth Information
The sarcoplasmic reticulum located throughout the myoplasm can be divided
into 3 main components: junctional (JSR), corbular (CSR), and network (NSR).
The sarcoplasmic reticulum indeed widens at multiple sites to form junctional SR
cisternae tightly coupled to the sarcolemma of T tubules. The junctional compart-
ment is positioned within 12 to 15 nm to T tubules. Together with the T tubule, JSR
defines a restricted subspace in which Ca
2
+
can reach high concentration. Junctional
sarcoplasmic reticulum contains the majority of the ryanodine receptors.
Calcium release from sarcoplasmic reticulum storage occurs at discrete loci in the
JSR-T tubule subspace — Ca
2
+
sparks, although other secondary Ca
2
+
transient
currents are initiated by other ion carriers. The corbular region is located near
the T tubules at a distance of several micrometers from the sarcolemma. Corbular
sarcoplasmic reticulum releases Ca
2
+
without interaction with sarcolemmal Ca
V
1.2
channels. Sarcoplasmic reticulum Ca
2
+
ATPases are predominantly located in
network sarcoplasmic reticulum.
In cardiomyocytes, the cardiac Ca
2
+
release unit is a JSR proteic complex that
comprises Ca
V
1.2 juxtaposed to ryanodine-sensitive, Ca
2
+
-release channel RyR2,
thereby achieving excitation-contraction coupling. This coupling is controlled
by RyR2-associated proteins and RyR2 phosphorylation. Junctional sarcoplasmic
reticulum unit includes ryanodin receptor RyR2, calsequestrin Casq2, junctin,
junctophilin-1 and -2, and triadin. Triadin-1 is the predominant isoform in car-
diomyocytes. The JSR complex is involved in Ca
2
+
release from the sarcoplasmic
reticulum by Ca
2
+
release units to trigger myocyte contraction, as well as buffer-
ing of stored Ca
2
+
in the lumen of the sarcoplasmic reticulum. In addition,
Ca
2
+
-induced Ca
2
+
release units exert a negative feedback on Ca
V
1.2 channels.
Conversely, muscle relaxation results from Ca
2
+
reuptake into the sarcoplasmic
reticulum by sarco(endo)plasmic reticulum Ca
2
+
ATPases.
Calsequestrin-2 sequesters Ca
2
+
inside the sarcoplasmic reticulum lumen,
avoiding Ca
2
+
leaks from its store during myocyte relaxation. Junctin docks
Casq2 to RyR2. Junctophilin-1 and -2 promote colocalization of Ca
V
1.2 with
RyR2. In addition, Aspartyl-asparaginyl
-hydroxylase (AspH) participates in
calcium storage in and release from the sarcoplasmic reticulum. Triadin anchors
calsequestrin Casq2 to RyR2 ryanodine receptors. Triadin maintains the structural
and functional integrity of the cardiac Ca
2
+
release units of the sarcoplasmic
reticulum [
341
].
Ca
2
+
-binding calmodulin and Ca
2
+
-calmodulin-dependent CamK2 kinase reg-
ulate activity of ryanodine receptors and phospholamban. Calmodulin mediates
Ca
2
+
-dependent channel inactivation.
Calcium-induced calcium release from the sarcoplasmic reticulum through ryan-
odine receptors initiated by Ca
2
+
influx through Ca
V
channels is an amplification
process relying on a positive feedback mechanism that governs cardiac inotropy.
Each cardiomyocyte produces a Ca
2
+
transient. The amplitude of Ca
2
+
transients
is determined by recruitment level of Ca
2
+
sparks (elementary Ca
2
+
sarcoplasmic
reticulum release signals), i.e., by increasing the number of RyR channels clustered
in spark-forming couplons. Sensitization and inhibition of RyR clusters shorten
and lengthen the interval between consecutive Ca
2
+
sparks, respectively [
342
].
β
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