Page 31 - Read Online

Strassheim et al. Vessel Plus 2018;2:29 I http://dx.doi.org/10.20517/2574-1209.2018.44 Page 3 of 22

Table 1. G protein-coupled receptor physiology and pathology in pulmonary hypertension
Physiology Ligand-receptor-reference Cell G-protein Important PH pathology
pathways
Vasodilation Adenosine-A 2A -AR; PGI 2 -IP [110-112] VSMC G s PKA +
EC-eNOS-NO Adenosine-A 2A -AR; Apelin- EC G i PKG +
dependent vasodilation APJ; Relaxin-RXFP; Opioid-
KOR [50,51,66,110-112,178,179,182,245,246]
Vasoconstriction ET1/ET A ; Ang II-AT1; TXA 2 -TP; PAF/ VSMC G q /G i Ca 2+ -
PAFR; Shingosine-1-P/S1P 1-5 ;
2+
Ca -CaSR [12,21,42,47,54-56,58,69,249,250]
Anti-inflammatory Adenosine-A 2A -AR; PGI 2 -IP [110] VSMC G s PKA +
PGI 2 -IP; adenosine-A 2A AR [232,239] Macrophage G s PKA +
PGI 2 -IP; adenosine-A 2A AR [110] Fibroblast G s PKA +
PGI 2 -IP; Adenosine-A 2A -AR [110] EC G s PKA +
Pro-inflammatory ET1-ET A ; MCP1-CCR2; RANTES-CCR5; VSMC G q /G i Ca 2+ -
TXA 2 -TP [69,163]
LTB 4 -LTB 4 R; MCP1-CCR2 [163,164] Macrophage G q /G i Ca 2+ -
PAF-PAFR; TXA 2 -TP [46,167,169] EC G q /G i Ca 2+ -
Cardiac myocyte AngII-AT 1 ; succinate-GPR91; thrombin- Cardiac myocyte G q /G i Ca 2+ -
hypertrophy PAR [205,206]
2+
Cardiac fibrosis Thrombin-PAR 1-4 [223,225] Cardiac fibroblast G q /G i /G 12 / 13 Ca /RhoA -
+: PH-protective; -: PH-pathogenic; VSMC: vascular smooth muscle cells; EC： endothelial cell

inhibits G - dependent activation of PLCb [21-23] . Vasodilator GPCRs that increase cAMP may also activate
q
cAMP-binding domain in exchange factor EPAC1, a GEF for the small molecular weight G-protein Rap1,
a member of Ras superfamily. Rap1 activates ARAP3, a Rho GAP, which in turn, inhibits RhoA, leading
to reduced MLC phosphorylation and vasodilation [24,25] . Vasodilation also occurs via endothelial cell (EC)-
dependent production of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS), which is activated
[26]
1177
by Akt or ERK1/2 by phosphorylation on Ser residue . Highly permeable NO readily enters VSMC,
2+
stimulates soluble guanylate cyclase (sGC) and activates cGMP-PKG, antagonizing Ca action on phospho-
19
2+
Ser -MLC and promoting vasodilation. More specifically, NO-sGC-cGMP-PKG-axis inhibits Ca increase
[27]
69
by stimulating TRPC6 phosphorylation at Thr , decreasing ROCE and increasing vasodilation . PKG
phosphorylates and activates RGS2, and RGS4, that leads to the inhibition of G/G ,-rergulated PLC activity
i
q
[23]
2+
and termination of the vasoconstrictor Ca signal . Both PKG and PKA phosphorylate and inhibit RhoA
and increase the activity of myosin light chain phosphatase (MLCP), thereby decreasing MLC contrac-
tion [28,29] . MLCP is also activated by vasodilators by PKG-mediated phosphorylation of a MLCP inhibitory
[20]
subunit . In addition, PKG and PKA reduce the ability of RhoA to inhibit the delayed rectifier potassium
2+
[30]
channel (KDR), which attenuates extracellular Ca entry . The enzyme PDE5A, a target of sildenafil
therapy in PH, hydrolyzes cGMP to counter the effects of NO-cGMP-PKG signaling. However, other PDEs,
[31]
including cAMP PDEs, play important roles . Vasoconstrictors activate PDE5A to reduce cGMP in VSMC
by RhoA/PKC-mediated inhibition of protein phosphatase 1 (PP1), thereby increasing phosphorylation of
[32]
PDE5A and activating it . GPCRs, including those for adenosine, ATP, adiponectin, apelin, prostaglandin
E2 (PGE2,), PGI2 generally increase NO from EC, which diffuses to VSMC, or directly increase cAMP in
VSMCs [33-39] .
As a final summation statement, all current PH therapies intersect GPCR actions by modulating critical
2+
signaling effects. Firstly they, ultimately inhibit intracellular Ca signaling and vasoconstriction. This in-
2+
cludes the cGMP-PDE inhibitors, soluble guanylate cyclase (sGC) activators, PGI2 analogs, Ca -channel
blockers, and ET-1 receptor antagonists. Secondly, they exert anti-inflammatory effects on vascular cells, as
all of these therapeutics are known to do [2,40,41] .
GPCR ligand-dependent vasoconstrictor response
Vasoconstrictor ligands, including ET-1, TxA , and serotonin are increased in serum of PH patients; for
2
serotonin a 4-5 fold increase has been reported, (8.8 ± 0.6 nmol/L) vs. (38.8 ± 7.3 nmol/L) [42-47] . Serotonin,