Biomedical Engineering Reference
In-Depth Information
5.5.2
Inositol Polyphosphate Messengers - Phosphoinositide
Sources
Therefore, whereas inositol (1,4,5)-trisphosphate is a major regulator of Ca
2
+
-based
responses in non-excitable cells, excitable cells such as cardiomyocytes employ
a coupled system of Ca
2
+
import (entry from the extracellular space and influx
from the intracellular stores through ryanodine receptors) rather than Ca
2
+
release
from the endoplasmic reticulum through IP
3
R receptors.
65
In ventriculomyocytes,
IP
3
R2 localizes mainly in the perinuclear region and nuclear envelope [
392
].
In atriomyocytes, IP
3
R2 content is 6 to 10 times larger than in ventriculomyocytes.
These receptors are detected in regions of the sarcoplasmic reticulum adjacent to
the sarcolemma, near ryanodine receptors.
Nonetheless, in human cardiomyocytes, a slight (1.5- to 2-fold) overall elevation
of PLC activity results from activation of
1-adrenergic or endothelin ET
A
receptors
(20- to 50-fold increase in non-excitable cells in response to angiotensin-2 and
acetylcholine) [
392
].
Inositol phospholipids, phosphatidylinositol, and its phosphorylated derivatives
lodge in cardiomyocyte sarcolemma in concentrations similar to those in other cell
types. Stimulated
α
1-adrenoceptors and ET
A
receptors in cardiomyocytes involve
primarily the generation of I(1,4)P
2
cleaved by PLC from PI(4)P agent [
392
].
Under normoxia, IP
3
production is limited. Whereas the IP
3
pool does not change
significantly upon stimulation,
66
concentrations of I(1,4)P
2
and IP
1
isomers
67
increase markedly upon receptor activation [
392
]. Messenger IP
3
is formed from
PI(4,5)P
2
by phospholipase-C. On the other hand, I(1,4,5)P
3
is rapidly processed by
I(1,4,5)P
3
3-kinases and membrane-linked I(1,4,5)P
3
5-phosphatases that deactivate
the IP
3
signal.
α
65
Receptor IP
3
RisaCa
2
+
channel on the endoplasmic reticulum, as Ca
2
+
concentration is much
greater than that of other cations. On the plasma membrane, it has a lower selectivity for divalent
than for monovalent cations; it may thus act as Na
+
or K
+
channels [
392
]. Plasmalemmal TRP
channels are much more selective for Ca
2
+
and enable Ca
2
+
entry into the cytosol. Receptor
IP
3
R can be phosphorylated by SRC family kinases, PKA, PKC, and Ca
2
+
-calmodulin-dependent
protein kinase CamK2. Most cell types contain multiple IP
3
R isoforms. Three IP
3
R isoforms
exist (IP
3
R1-IP
3
R3); IP
3
R1 possesses 3 splice variants; IP
3
R2 splice variants are not functional.
Affinity for IP
3
of IP
3
R2 is higher than that IP
3
R1, which is greater than that of IP
3
R3. In the heart,
IP
3
R1 predominates in nodal (conducting) myocytes; IP
3
R2 in contracting myocytes. Yet, IP
3
Rin
adult myocardium is 50-fold less abundant than ryanodine RyR2 receptor [
392
].
66
Except in ischemia upon receptor activation (e.g., after noradrenaline release from sympathetic
nerves) and transiently upon reperfusion. Production of I(1,4,5)P
3
can cause arrhythmias [
392
]. In
atriomyocytes, synthesized I(1,4,5)P
3
can bind to subsarcolemmal IP
3
R close to its generation site,
causing local cytosolic Ca
2
+
level increases that disturb adjacent ion carriers, specifically Ca
V
1.2
channel and Na
+
-Ca
2
+
exchanger.
67
Compounds with the same molecular formula but different structural formulas. Geometrical
positioning of atoms varies. Inositol monophosphates include I(1)P, I(2)P, and I(4)P isomers.
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