Biomedical Engineering Reference
In-Depth Information
TRPC3),
17
store-operated Ca
2
+
channels,
18
and large-conductance Ca
2
+
-activated
K
+
channels (BK),
19
which lodge in caveolae where the sarco(endo)plasmic
reticulum and plasma membrane are in close proximity [
717
].
In airway and vascular smooth myocytes, proximity (distance
30 nm) between
mitochondria and sarco(endo)plasmic reticulum enables local signaling between
these 2 organelles. In particular, IP
3
R regulates mitochondrial Ca
2
+
concentration.
Mitochondrial Ca
2
+
uniporter, the major mitochondrial Ca
2
+
uptake axis, is sensi-
tive to micromolar Ca
2
+
levels. IP
3
R-mediated Ca
2
+
waves increase mitochondrial
Ca
2
+
concentration, stimulate ROS generation and NF
∼
κ
B, and foster Ca
V
1.2 gene
expression in cerebral artery smooth myocytes [
717
].
Conversely, mitochondria regulate IP
3
R in smooth myocytes, as they: (1) buffer
local and global elevation in cytosolic Ca
2
+
level; (2) control ATP synthesis;
20
(3) participate in ROS signaling;
21
and modulate ion channels that regulate mem-
brane potential and cytosolic Ca
2
+
level. In vascular smooth myocytes, mitochon-
dria regulate the activity of several plasmalemmal ion channels, such as voltage-
dependent Ca
2
+
,Ca
2
+
-activated K
+
,Ca
2
+
-activated Cl
−
(ClCa), and store-operated
Ca
2
+
channels, thereby influencing membrane potential and Ca
2
+
signals [
717
].
Inositol trisphosphate receptors controls not only cell contraction, but also
gene expression and cell migration and proliferation. In cerebral artery smooth
myocytes, IP
3
R-mediated Ca
2
+
release activates NF
κ
B directly and indirectly via
mitochondrial ROS production; NF
1c subunit
expression [
717
]. Cell proliferation correlates with an elevation in IP
3
R1 production
in aortic and carotid artery smooth myocytes and upregulation of all IP
3
R isoforms
in mesenteric artery smooth myocytes [
717
].
κ
B stimulates Ca
V
1.2 channel
α
17
An elevation in intracellular IP
3
concentration supports coupling of IP
3
R1 to transient receptor
potential canonical channel TRPC3 in arterial smooth myocytes, hence causing a depolarization
that stimulates Ca
V
channel. Subsequent global intracellular Ca
2
+
concentration elevation pro-
vokes vasoconstriction. IP
3
R-mediated Ca
2
+
release also activates Ca
2
+
-sensitive PKC isoforms
that stimulate PKC-dependent TRPC1 in portal vein smooth myocytes [
717
]. In cerebral artery
smooth myocytes, Ca
2
+
-sensitive TRPM4 is regulated by released Ca
2
+
, but not by direct
interaction with IP
3
R in the absence of C-terminal calmodulin- and IP
3
R-binding (CIRB) domain.
18
I.e., Orai protein, in addition to TRPC1 and TRPC5 to TRPC7 channels in smooth myocytes of
coronary and mesenteric arteries, pulmonary arteries, inferior vena cava, and portal vein.
19
Activated IP
3
R1 increases the Ca
2
+
sensitivity of nearby BK channels, especially in cerebral
artery smooth myocytes, thereby facilitating channel activation at lower Ca
2
+
concentrations.
Resulting hyperpolarization inhibits Ca
V
channel, thereby amplifying stimulation by released Ca
2
+
to oppose IP
3
-induced smooth myocyte contraction and favoring vasodilation.
20
Agent ATP enhances sensitivity of IP
3
RtoIP
3
and Ca
2
+
. Moreover, it is required for SERCA
activity.
21
Mitochondrial ROS may modulate IP
3
R expression and activity.
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