Biomedical Engineering Reference
In-Depth Information
G-Protein-Coupled Receptors
Immersed in strain and stress fields, mechanosensors at the surface of vessel
wall cells detect these signals and relay them via chemical reaction cascades
that control the phosphorylation state of myosin light chain, hence actin-myosin
interactions. In addition to membrane depolarization primed by mechanically gated
ion channels, certain types of integrins (e.g.,
α
5
β
1
-integrins) can
operate as mechanotransducers that may cause phosphorylation of Ca
V
and BK
ion channels. Furthermore, among G-protein-coupled receptors that are commonly
activated by chemical compounds (peptides, lipids, nucleotides, and amines; Vol. 3-
Chap. 7. G-Protein-Coupled Receptors), mechanosensitive GPCRs trigger mainly
G
α
V
β
3
-and
α
q
/
11
and G
α
12
/
13
intracellular signaling pathways [
796
].
Gq/11-Coupled Receptors and the PLC-IP
3
/DAG-Ca
2
+
/PKC Pathway
Receptors coupled to the Gq/11 subclass activate phospholipase-C
that generates
IP
3
, thereby causing Ca
2
+
influx from endoplasmic reticulum store through IP
3
receptors. Calcium-calmodulin causes phosphorylation of myosin light chain ki-
nase. The other generated messenger, diacylglycerol, stimulates protein kinase-C
that phosphorylates PP1
r14a
inhibitory subunit,
72
and inhibits myosin light chain
phosphatase. In addition, diacylglycerol directly activates TRPC3 and TRPC6
channels, thereby causing Ca
2
+
entry, in addition to a coordinated interaction of
IP
3
R and TRPC3 channels [
796
]. Moreover, PKC phosphorylates and, in synergy
with intracellular ATP and calmodulin, activates TRPM4 channels. Both TRPP1 and
TRPP2 may also be involved in pressure sensing.
β
G12/13-Coupled Receptors and the RhoA-RoCK Axis
Receptors coupled to the G12/13 subclass activate Rho guanine nucleotide-
exchange factor (RhoGEF) that stimulates RhoA GTPase. The latter targets RoCK
kinase that phosphorylates MLCP, thus impeding MLC dephosphorylation.
Prostanoid Receptors
In response to smooth myocyte stretching resulting to increased wall tension due
to elevated luminal pressure, phospholipase-A2 creates arachidonic acid that is
metabolized into thromboxane-A2 and 20-hydroxyeicosatetraenoic acid by cy-
clooxygenase and cytochrome-P450, respectively. Agent 20HETE not only inhibits
72
A.k.a. 17-kDa substrate phosphatase inhibitor of PP1 (CPI17).
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