The generation of nitric oxide by G protein-coupled receptors

doi:10.1016/S0024-3205(98)00348-8

Life Sciences

Volume 64, Issue 1, 27 November 1998, Pages 1-15

https://doi.org/10.1016/S0024-3205(98)00348-8 Get rights and content

Abstract

The highly reactive free radical gas, nitric oxide, serves a variety of biomodulatory functions and has been implicated in a growing array of physiological and pathophysiological states. The striking differences between this labile substance and other, more conventional, signaling moleculés highlight the tight degree of nitric oxide regulation that is required in order to maintain appropriate cellular homeostasis. The generation of nitric oxide represents a common component of the signal transduction pathways of a number of chemical signaling molecules that act via binding to G protein-coupled receptors. This review focuses on the relationship between this receptor superfamily, the generation of nitric oxide via the actions of the nitric oxide synthases and some of the inter- and intracellular roles of nitric oxide.

References (104)

S.H. Snyder et al.
Trends Pharmacol. Sci.
(1991)
D.S. Bredt et al.
Neuron
(1992)
T. Deguchi et al.
J. Biol. Chem.
(1982)
H. Kimura et al.
J. Biol. Chem.
(1975)
J. Garthwaite et al.
Eur. J. Pharmacol.
(1989)
L. Busconi et al.
J. Biol. Chem.
(1993)
J.E. Brenman et al.
Cell
(1996)
C.M. Arroyo et al.
Biochem. Biophys. Res. Comm.
(1990)
K. Yamada et al.
Neurosci. Res.
(1997)
M. McKinney et al.
Eur. J. Pharmacol.
(1990)

G.B. Stefano et al.

Brain Res.

(1997)

M.P. Caulfield

Pharmac. Ther.

(1993)

G. Pilar et al.

Life Sci.

(1996)

H. Karaki et al.

Eur. J. Pharmacol.

(1988)

G.C. Ormandy et al.

Neurosci. Lett.

(1989)

D.S. McGehee et al.

Neuron

(1992)

A. Miyamoto et al.

J. Biol. Chem.

(1997)

P.F. Méry et al.

J. Biol. Chem.

(1993)

I.D.G. Duarte et al.

Eur. J. Pharmacol.

(1990)

I.D.G. Duarte et al.

Eur. J. Pharmacol.

(1992)

H.M. Lander et al.

J. Biol. Chem.

(1995)

H.M. Lander et al.

J. Biol. Chem.

(1996)

Z. Ni et al.

Kidney International

(1997)

S. Ceccatelli

Brain Res. Bull.

(1997)

G. Bagetta et al.

Eur. J. Pharmacol.

(1992)

G. Bagetta et al.

Biochem. Biophys. Res. Comm.

(1993)

H.G. Dohlman et al.

Annu. Rev. Pharmacol.

(1991)

T.M. Dawson et al.

J. Neurosci.

(1994)

J. Garthwaite et al.

Annu. Rev. Physiol.

(1995)

R.F. Furchgott et al.

Nature

(1980)

D.R. Wotta et al.

Drug Develop. Res.

(1997)

S.H. Snyder et al.

Sci. Amer.

(1992)

L.C. Green et al.

Science

(1981)

R. Iyegnar et al.

J.B. Hibbs et al.

J. Immunol.

(1987)

J.B. Hibbs et al.

L.J. Ignarro et al.

J. Pharmacol. Exp. Ther.

(1981)

R.M.J. Palmer et al.

Nature

(1987)

L.J. Ignarro et al.

Circ. Res.

(1987)

S. Moncada et al.

Pharmacol. Rev.

(1991)

M.J. Rand

Clin. Exp. Pharmacol. Physiol.

(1992)

H. Kimura et al.

Nature

(1975)

W.P. Arnold et al.

J. Garthwaite et al.

Nature

(1988)

D.S. Bredt et al.

R.G. Knowles et al.

S. Moncada et al.

Pharmacol. Rev.

(1997)

D.S. Bredt et al.

J.L. Dinerman et al.

J.H.M. Cabral et al.

Nature

(1996)

Cited by (45)

B-type allatostatin modulates immune response in hepatopancreas of the mud crab Scylla paramamosain
2020, Developmental and Comparative Immunology
B-type allatostatin (AST-B) is a pleiotropic neuropeptide, widely found in arthropods. However, the information about its immune effect in crustaceans is unknown. In this study, we identified the nervous tissue as the main site for Sp-AST-B expression, while its receptor gene (Sp-AST-BR) is widely expressed in various tissues, including the hepatopancreas. This suggests the peptide's potential role in diverse physiological processes in the mud crab Scylla paramamosain. In situ hybridization revealed that Sp-AST-BR is mainly localized in the F-cell of hepatopancreas. Furthermore, we found a significant up-regulation of Sp-AST-BR transcripts in the hepatopancreas following exposure to lipopolysaccharide (LPS) or polyriboinosinic polyribocytidylic acid (Poly (I:C)). Results from in vitro and in vivo experiments revealed that treatment with a synthetic AST-B peptide mediated significant upregulation in expression of AST-BR, nuclear factor-κB (NF-κB) pathway components (Dorsal and Relish), pro-inflammatory cytokine (IL-16) and antimicrobial peptides (AMPs) in the hepatopancreas. In addition, AST-B treatment mediated significant elevation of nitric oxide (NO) production and enhanced the bacteriostasis capacity of the hepatopancreas tissue in vitro. Taken together, these findings reveal the existence of a basic neuroendocrine-immune (NEI) network in crabs, and indicate that AST-B could couple with its receptor to trigger downstream signaling pathways and induce immune responses in the hepatopancreas.
Short neuropeptide F enhances the immune response in the hepatopancreas of mud crab (Scylla paramamosain)
2020, Fish and Shellfish Immunology
Short neuropeptide F (sNPF), a highly conserved neuropeptide, displays pleiotropic functions on multiple aspects of physiological processes, such as feeding, metabolic stress, locomotion, circadian clock and reproduction. However, to date there has no any report on the possible immunoregulation of sNPF in crustaceans. In the present study, we found that the Sp-sNPF was mainly expressed in the nervous tissue in the mud crab Scylla paramamosain, while the sNPF receptor gene (Sp-sNPF-R) was expressed in a wide variety of tissues, including the hepatopancreas. In situ hybridization further showed that the Sp-sNPF-R positive signal mainly localized in the F-cells of the hepatopancreas. Moreover, the Sp-sNPF-R transcription could be significantly up-regulated after the challenge of bacteria-analog LPS or virus-analog Poly (I:C). Both in vitro and in vivo experiments showed that the synthetic sNPF peptide significantly increased the gene expressions of sNPF-R, nuclear factor-κB (NF-κB) signaling genes and antimicrobial peptides (AMPs) in the hepatopancreas. Simultaneously, the administration of sNPF peptide in vitro also increased the concentration of nitric oxide (NO) and the bacteriostasis of the culture medium of hepatopancreas. These results indicated that sNPF up-regulated hepatopancreas immune responses, which may bring new insight into the neuroendocrine-immune regulatory system in crustacean species, and could potentially provide a new strategy for disease prevention and control for mud crab aquaculture.
Effects of selective and non-selective inhibitors of nitric oxide synthase on morphine- and endomorphin-1-induced analgesia in acute and neuropathic pain in rats
2013, Neuropharmacology
Nitric oxide (NO) has been reported to be involved in the mechanisms of pain generation throughout the nervous system. We examined the effects of intrathecally (i.t.) administered nitric oxide synthase (NOS) inhibitors on the antinociceptive effects of morphine and endomorphin-1 during acute pain and in chronic constriction injury (CCI)-exposed rats. We used N^G-nitro-l-arginine methyl ester (l-NAME), a non-selective NOS inhibitor; 7-nitroindazole (7-NI) or 1-(2-trifluoromethyl-phenyl)-imidazole (TRIM), selective inhibitors of neuronal NOS (NOS1); and 1400W dihydrochloride, a selective inhibitor of inducible NOS (NOS2). Morphine (0.5–2.5 μg) and endomorphin-1 (2.5–20 μg) in acute pain and morphine (10–40 μg) and endomorphin-1 (5–20 μg) after CCI-injury were combined with NOS inhibitors. For acute pain, the ED₅₀ for endomorphin-1 (7.1 μg) was higher than that of morphine (1.3 μg) in the tail-flick test. For neuropathic pain, the ED₅₀ value for morphine was much higher (43.2 μg) than that of endomorphin-1 (9.2 μg) in von Frey test. NOS inhibitors slightly influenced pain thresholds in both pain models. Moreover, in neuropathic pain, the effects of morphine were more potentiated by l-NAME, TRIM, 7-NI and 1400W (12×, 8.6×, 4.1× and 5.3×, respectively) than were the effects of endomorphin-1 (2.7×, 4.3×, 3.4× and 2.1×, respectively) in the von Frey test. Minocycline which is known to enhance the efficiency of morphine in neuropathic pain, decreased the mRNA expression of NOS1 in the DRG and NOS2 and C1q in the spinal cord after CCI. Both NOS2 and IBA-1 protein levels in the spinal cord and NOS1, NOS2 and IBA1 protein levels in DRG decreased after minocycline administration. In conclusion, our results provide evidence that both neuronal and non-neuronal NOS/NO pathways contribute to the behavioural pain responses evoked by nerve injury. The NOS inhibitors regardless of the type of pain enhanced morphine antinociception and, to a lesser extent, altered the effects of endomorphin-1, an opioid ligand with a peptidergic structure.
Regulator of G protein signaling 2 deficiency causes endothelial dysfunction and impaired endothelium-derived hyperpolarizing factor-mediated relaxation by dysregulating G <inf>i/o</inf> signaling
2012, Journal of Biological Chemistry
Citation Excerpt :
Endothelial GPCRs such as M3 muscarinic and B2 bradykinin receptors couple to the Gq/11 class of heterotrimeric G proteins to activate phospholipase Cβ, which hydrolyzes phosphatidylinositol 4,5-bisphosphate to form diacylglycerol, which activates protein kinase C, and inositol 1,4,5-trisphosphate, which releases Ca2+ from intracellular stores. Increased intracellular Ca2+ levels activate endothelial nitric-oxide synthase (eNOS) to produce NO (2), phospholipase activity to produce arachidonic acid and its metabolites (7), and calcium-activated small (SKCa) and intermediate (IKCa) conductance potassium channels to hyperpolarize endothelium and vascular smooth muscle (1, 3). Indeed, mice lacking eNOS or IKCa and SKCa activity exhibit endothelial dysfunction and hypertension (8).
Regulator of G protein signaling 2 (RGS2) is a GTPase-activating protein for G_q/11α and G_i/oα subunits. RGS2 deficiency is linked to hypertension in mice and humans, although causative mechanisms are not understood. Because endothelial dysfunction and increased peripheral resistance are hallmarks of hypertension, determining whether RGS2 regulates microvascular reactivity may reveal mechanisms relevant to cardiovascular disease. Here we have determined the effects of systemic versus endothelium- or vascular smooth muscle-specific deletion of RGS2 on microvascular contraction and relaxation. Contraction and relaxation of mesenteric resistance arteries were analyzed in response to phenylephrine, sodium nitroprusside, or acetylcholine with or without inhibitors of nitric oxide (NO) synthase or K⁺ channels that mediate endothelium-derived hyperpolarizing factor (EDHF)-dependent relaxation. The results showed that deleting RGS2 in vascular smooth muscle had minor effects. Systemic or endothelium-specific deletion of RGS2 strikingly inhibited acetylcholine-evoked relaxation. Endothelium-specific deletion of RGS2 had little effect on NO-dependent relaxation but markedly impaired EDHF-dependent relaxation. Acute, inducible deletion of RGS2 in endothelium did not affect blood pressure significantly. Impaired EDHF-mediated vasodilatation was rescued by blocking G_i/oα activation with pertussis toxin. These findings indicated that systemic or endothelium-specific RGS2 deficiency causes endothelial dysfunction resulting in impaired EDHF-dependent vasodilatation. RGS2 deficiency enables endothelial G_i/o activity to inhibit EDHF-dependent relaxation, whereas RGS2 sufficiency facilitates EDHF-evoked relaxation by squelching endothelial G_i/o activity. Mutation or down-regulation of RGS2 in hypertension patients therefore may contribute to endothelial dysfunction and defective EDHF-dependent relaxation. Blunting G_i/o signaling might improve endothelial function in such patients.
Homologous desensitization of signalling by the alpha (α) isoform of the human thromboxane A<inf>2</inf> receptor: A specific role for nitric oxide signalling
2007, Biochimica et Biophysica Acta - Molecular Cell Research
Thromboxane (TX) A₂ plays a central role in hemostasis, regulating platelet activation status and vascular tone. We have recently established that the TPβ isoform of the human TXA₂ receptor (TP) undergoes rapid, agonist-induced homologous desensitization of signalling largely through a G protein-coupled receptor kinase (GRK) 2/3-dependent mechanism with a lesser role for protein kinase (PK) C. Herein, we investigated the mechanism of desensitization of signalling by the TPα isoform. TPα undergoes profound agonist-induced desensitization of signalling (intracellular calcium mobilization and inositol 1,4,5 trisphosphate generation) in response to the TXA₂ mimetic U46619 but, unlike that of TPβ, this is independent of GRKs. Similar to TPβ, TPα undergoes partial agonist-induced desensitization that occurs through a GF 109203X-sensitive, PKC mechanism where Ser¹⁴⁵ within intracellular domain (IC)₂ represents the key phospho-target. TPα also undergoes more profound sustained PKC- and PKG-dependent desensitization where Thr³³⁷ and Ser³³¹, respectively, within its unique C-tail domain were identified as the phospho-targets. Desensitization was impaired by the nitric oxide synthase (NOS), soluble guanylyl cyclase (sGC) and PKG inhibitors l-NAME, LY 83583 and KT5823, respectively, indicating that homologous desensitization of TPα involves nitric oxide generation and signalling. Consistent with this, U46619 led to rapid phosphorylation/activation of endogenous eNOS. Collectively, data herein suggest a mechanism whereby agonist-induced PKC phosphorylation of Ser¹⁴⁵ partially and transiently impairs TPα signalling while PKG- and PKC-phosphorylation at both Ser³³¹ and Thr³³⁷, respectively, within its C-tail domain profoundly desensitizes TPα, effectively terminating its signalling. Hence, in addition to the agonist-mediated PKC feedback mechanism, U46619-activation of the NOS/sGC/PKG pathway plays a significant role in inducing homologous desensitization of TPα.
Regulation of neuronal nitric-oxide synthase activity by somatostatin analogs following SST5 somatostatin receptor activation
2006, Journal of Biological Chemistry
Somatostatin receptor SST5 is an inhibitory G protein-coupled receptor that exerts a strong cytostatic effect on various cell types. We reported previously that the SST5 anti-proliferative effect results in the inhibition of mitogen-induced increases in intracellular cGMP levels and MAPK activity. This study was conducted to define the early molecular events accountable for the SST5-mediated anti-proliferative effect. Here, we demonstrate that, in Chinese hamster ovary cells expressing SST5 (CHO/SST5 cells), somatostatin inhibited cell proliferation induced by nitric oxide donors and overexpression of the neuronal nitric-oxide synthase (nNOS) protein isoform. Accordingly, nNOS activity and dimerization were strongly inhibited following SST5 activation by the somatostatin analog RC-160. In CHO/SST5 cells, nNOS was dynamically recruited by the SST5 receptor and phosphorylated at tyrosyl residues following RC-160 treatment. RC-160 induced SST5-p60^src kinase complex formation and subsequent p60^src kinase activation. Coexpression of an inactive p60^src kinase mutant with SST5 blocked RC-160-induced nNOS phosphorylation and inactivation and prevented the SST5-mediated anti-proliferative effect. In CHO/SST5 cells, p60^src kinase associated with nNOS to induce its inactivation by phosphorylation at tyrosyl residues following RC-160 treatment. Using recombinant proteins, we demonstrated that such phosphorylation prevented nNOS homodimerization. Next, surface plasmon resonance and mutation analysis revealed that p60^src directly associated with nNOS phosphorylated Tyr⁶⁰⁴. SST5-mediated inhibition of nNOS activity was demonstrated to be essential to the RC-160 anti-proliferative effect on pancreatic endocrine tumor-derived cells. We therefore identified nNOS as a new p60^src kinase substrate essential for SST5-mediated anti-proliferative action.

View all citing articles on Scopus

View full text

MinireviewThe generation of nitric oxide by G protein-coupled receptors

Abstract

Trends Pharmacol. Sci.

Neuron

J. Biol. Chem.

J. Biol. Chem.

Eur. J. Pharmacol.

J. Biol. Chem.

Cell

Biochem. Biophys. Res. Comm.

Neurosci. Res.

Eur. J. Pharmacol.

Brain Res.

Pharmac. Ther.

Life Sci.

Eur. J. Pharmacol.

Neurosci. Lett.

Neuron

J. Biol. Chem.

J. Biol. Chem.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

J. Biol. Chem.

J. Biol. Chem.

Kidney International

Brain Res. Bull.

Eur. J. Pharmacol.

Biochem. Biophys. Res. Comm.

Annu. Rev. Pharmacol.

J. Neurosci.

Annu. Rev. Physiol.

Nature

Drug Develop. Res.

Sci. Amer.

Science

J. Immunol.

J. Pharmacol. Exp. Ther.

Nature

Circ. Res.

Pharmacol. Rev.

Clin. Exp. Pharmacol. Physiol.

Nature

Nature

Pharmacol. Rev.

Nature

Minireview
The generation of nitric oxide by G protein-coupled receptors