Biomedical Engineering Reference
In-Depth Information
.
7
Both isoforms have several common
substrates, such as inositol (1,4,5)-trisphosphate receptor (IP
3
R)-associated cGMP
kinase substrate (IRAG),
8
myosin-binding PP1
r12a
regulatory subunit, and regulator
RGS2 of G-protein signaling.
Enzyme PKG1
α
β
kinase isozymes PKG1
and PKG1
β
phosphorylates PP1
r12a
, hence causing calcium desensitization
of myosin regulatory light chain. It also targets RGS2, thereby modulating receptor-
mediated signaling via Gq/11 class of G-protein subunits. It interacts specifically
with IRAG protein that is highly expressed in the membrane of the endoplasmic
reticulum of smooth myocytes. It allows stable interaction of IP
3
R1 receptor with
PKG1
β
enzyme [
716
].
8.3.5
Inositol Trisphosphate Receptors and Calcium Release
Entry of extracellular calcium can occur through plasma membrane ion carriers,
such as voltage-dependent Ca
V
1.2 channels, non-selective cation channels, and
Na
+
-Ca
2
+
exchangers. Intracellular calcium signals are also produced by Ca
2
+
2+
release from intracellular stores (sarco[endo]plasmic reticulum and mitochondria).
In smooth myocytes, calcium signals include Ca
2
+
flashes
,
9
oscillations
,
10
puffs
,
11
ripples
,
12
sparklets
,
sparks
,
13
waves
,
14
and global intracellular Ca
2
+
con-
centration elevation (Table
8.3
).
15
Activated IP
3
R generates these cues. However,
non-selective cation, store-operated Ca
2
+
, ryanodine-sensitive Ca
2
+
release, tran-
sient receptor potential, and voltage-dependent Ca
2
+
channels also contribute to
and modulate these calcium signals.
7
A.k.a. cGK1
, respectively.
8
A.k.a. murine retrovirus integration site homolog MRVI1.
9
Rapid calcium flashes observed during rhythmic phasic contractions of smooth myocytes rely on
voltage-dependent Ca
2
+
channels, IP
3
Rs, and ryanodine-sensitive Ca
2
+
channels.
10
Repetitive, non-propagating, global elevations of intracellular Ca
2
+
concentration generated by
periodic release from sarco(endo)plasmic reticulum of Ca
2
+
in smooth myocytes due to cyclical
positive and negative feedback of intracellular Ca
2
+
concentration on IP
3
R channel activity with
contributions from ryanodine-sensitive Ca
2
+
and canonical transient receptor potential channels.
11
Calcium puffs arise from the synchronous opening of about 30 IP
3
R channels (cluster size
∼
α
and cGK1
β
400 nm) with a minor contribution from ryanodine-sensitive Ca
2
+
channels.
12
Spontaneous, low-amplitude, propagating, IP
3
R-mediated Ca
2
+
signals following PLC activa-
tion and Ca
2
+
release.
13
Localized, intracellular Ca
2
+
transients that result from the concerted opening of ryanodine-
sensitive Ca
2
+
channels. IP
3
R receptors can contribute to Ca
2
+
sparks.
14
Propagating
Ca
2
+
elevations
in
intracellular
concentration
due
to
release
from
sarco(endo)plasmic reticulum upon activation of IP
3
R and RyR receptors.
15
These events result from IP
3
R activation that stimulates plasmalemmal TRPC1, TRPM4, and
voltage-dependent Ca
2
+
channels.
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