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Page 2 of 22 Strassheim et al. Vessel Plus 2018;2:29 I http://dx.doi.org/10.20517/2574-1209.2018.44

Increased pressure initially results in compensatory cardiac hypertrophy, but eventually causes de-com-
pensatory cardiac remodeling and death by heart failure. Recent research indicates that PH in all its forms,
[1]
especially associated with left heart disease, is more common than previously thought . Current PH thera-
pies that include endothelin-1 (ET1) receptor antagonists, prostacyclin analogs, cGMP- phosphodiesterase
2+
(PDE) inhibitors, and Ca channel blockers impede, but do not stop the disease process, emphasizing the
[2]
need for a finding of alternate treatments . Over the years, preclinical research in PH has identified many
protein targets, but very few have translated to the bench side. By contrast, G-protein-coupled receptors
(GPCRs), the largest superfamily in the genome, play an important role in the development of PH and can
[3]
be easily targeted by drugs . The heart, a prime target for development of new PH therapies, expresses 200
GPCRs . GPCR signaling cascades are critical for cardiovascular function and are targeted for the treat-
[4]
ment of hypertension and heart failure by agonist and antagonist strategies. Here we reviewed the current
knowledge on GPCR signaling in cardiac, vascular, and blood cells and highlighted some critical outcomes
in PH, such as vasoconstriction/vasodilation responses, vascular inflammation, vascular and cardiac re-
modeling, and endothelial dysfunction (ED).

GPCR-MEDIATED SIGNALING
GPCRs are a family of 7-transmembrane domain proteins, forming a deep binding pocket for the extracel-
lular ligand, agonist, which activates the receptor. Intracellular loops make contact to heterotrimeric G-
[5]
proteins of 4 different classes (Ga , Ga, Ga , Ga ) [Table 1] . Agonist binding to GPCRs stimulates GDP/
i
s
q
12
GTP exchange on Ga subunits, converting them into the active state and promote dissociation of Gbg
subunits. G proteins interact with multiple effectors, leading to generation of second messengers, includ-
2+
ing cAMP, 1,2-diacylglycerol, phosphatidylinositol-3, 4, 5-trisphosphate (PIP3), and Ca . These signaling
events are translated into complex hierarchy of kinase network [PKA, PKC, Akt, Ca /calmodulin-dependent
2+
protein kinase (CAMK)] leading to the regulation of gene expression and cellular functions. There are four
families of Ga subunits with multiple members. as exists as multiple transcripts 42 short and 44kD long
forms. a subfamily has a , a , a , a , a , a ; the a subfamily has a ,a , and a and the a family. The
i3
11
12/13
I
i1
14
O2
16;
O1
q
z
i2
b subunits are b ; and the g subunits are g 1-5,7,8,10,11,13 . The bg subunits, like Ga subunits, activate intracellular
1-5
effector pathways including MAPK cascades, Rac1, phospholipase C-b (PLC-b, phosphoinositide 3 kinase
g (PI3K-g, and ion channels and show variation as to the GPCR-Ga -complexes they interact with. Termi-
nation of G protein activation cycle occurs by the transition of Ga subunits to GDP-bound state, that is
catalyzed by GTPase activating proteins (GAPs), known as regulators of G-protein signaling (RGS proteins).
There are 31 proteins, containing the RGS domain that function as GTPase enzymes, terminating G-protein
signaling .
[6,7]
GPCR SIGNALING IN VASOCONSTRICTION AND VASCULAR REMODELING
19
2+
Vasoconstriction is driven by Ca -dependent phosphorylation of myosin light chain (MLC) on Ser -MLC,
whereas vasodilators oppose this event [8-10] [Figure 1, Tables 1 and 2]. In vascular smooth muscle cells
(VSMC), the vasoconstrictor response is mediated by G , G , or G 12/13 -coupled GPCRs for ET1, angiotensin
i-
q-
2+
II (Ang II), serotonin, and thrombin [11-16] . G and G activate PLC pathways, increasing Ca and receptor
i
q
operated calcium entry (ROCE) via transient receptor potential cation channel subfamily C member 6
(TRPC ) channels. TRPC -activation occurs by several mechanisms, including direct ERK1/2-mediated
6
6
phosphorylation of TRPC6. Secondly, phosphoinositide-4, 5-bisphosphate (PIP ), the substrate for PLC, is
2
an inhibitor of TRPC 6 [17,18] . Activation of G 12/13 by vasoconstrictor GPCRs stimulates G 12/13 -dependent RhoA
GEFs to increase the activity of, RhoA. In turn, RhoA activates Rho associated kinase (ROCK), which leads
19
to increased Ser -MLC and thereby, vasoconstriction [19,20] . Vasodilators, such as prostaglandin I (PGI ),
2
2
2+
acting via G -coupled (IP) receptor on VSMC, activate PKA and decrease intracellular Ca , leading to re-
s
19
duced MLC phosphorylation on Ser [Figure 1, Table 1].
2+
Vasodilators decrease intracellular Ca by inhibiting PLCb and TRPC . The mechanism involves PKA/
6
28
PKG-mediated phosphorylation of PLCb and TRPC (on Ser ) and by phosphorylation of RGS4, which
6