Expression and function of NPSR1/GPRA in the lung before and after induction of asthma-like disease

Allen, Irving C.; Pace, Amy J.; Jania, Leigh A.; Ledford, Julie G.; Latour, Anne M.; Snouwaert, John N.; Bernier, Virginie; Stocco, Rino; Therien, Alex G.; Koller, Beverly H.

doi:10.1152/ajplung.00174.2006

Cited by 60 publications

(60 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although HGPRT-deficient cells display normal proliferation in vitro (due to unaffected purine de novo synthesis), HGPRT is indispensable in vivo. The level of HPRT1 mRNA was found to be reduced in inflamed lung tissue (Allen et al, 2006). No data have yet been reported on the tissue distribution or metabolism of T-705 in vivo.…”

Section: Discussionmentioning

confidence: 87%

Role of Human Hypoxanthine Guanine Phosphoribosyltransferase in Activation of the Antiviral Agent T-705 (Favipiravir)

Naesens

Guddat

Keough

et al. 2013

Molecular Pharmacology

108

152

View full text Add to dashboard Cite

6-Fluoro-3-hydroxy-2-pyrazinecarboxamide (T-705) is a novel antiviral compound with broad activity against influenza virus and diverse RNA viruses. Its active metabolite, T-705-ribose-59-triphosphate (T-705-RTP), is recognized by influenza virus RNA polymerase as a substrate competing with GTP, giving inhibition of viral RNA synthesis and lethal virus mutagenesis. Which enzymes perform the activation of T-705 is unknown. We here demonstrate that human hypoxanthine guanine phosphoribosyltransferase (HGPRT) converts T-705 into its ribose-59-monophosphate (RMP) prior to formation of T-705-RTP. The anti-influenza virus activity of T-705 and T-1105 (3-hydroxy-2-pyrazinecarboxamide; the analog lacking the 6-fluoro atom) was lost in HGPRT-deficient Madin-Darby canine kidney cells. This HGPRT dependency was confirmed in human embryonic kidney 293T cells undergoing HGPRT-specific gene knockdown followed by influenza virus ribonucleoprotein reconstitution.Knockdown for adenine phosphoribosyltransferase (APRT) or nicotinamide phosphoribosyltransferase did not change the antiviral activity of T-705 and T-1105. Enzymatic assays showed that T-705 and T-1105 are poor substrates for human HGPRT having K m app values of 6.4 and 4.1 mM, respectively. Formation of the RMP metabolites by APRT was negligible, and so was the formation of the ribosylated metabolites by human purine nucleoside phosphorylase. Phosphoribosylation and antiviral activity of the 2-pyrazinecarboxamide derivatives was shown to require the presence of the 3-hydroxyl but not the 6-fluoro substituent. The crystal structure of T-705-RMP in complex with human HGPRT showed how this compound binds in the active site. Since conversion of T-705 by HGPRT appears to be inefficient, T-705-RMP prodrugs may be designed to increase the antiviral potency of this new antiviral agent.

show abstract

Section: Discussionmentioning

confidence: 87%

Role of Human Hypoxanthine Guanine Phosphoribosyltransferase in Activation of the Antiviral Agent T-705 (Favipiravir)

Naesens

Guddat

Keough

et al. 2013

Molecular Pharmacology

108

152

View full text Add to dashboard Cite

show abstract

“…For example, Allen and co-workers did not detect expression of GPRA in human lung tissue or in mice with ovalbumin-induced lung inflammation. 10 They also reported that GPRAdeficient mice showed the same allergic airway inflammation responses as the wild-type mice after ovalbumin challenge followed by aerosols of antigen exposure. 10 SNPs in GPRA have been associated with asthma and atopy susceptibility in Caucasians and Asians.…”

Section: Discussionmentioning

confidence: 91%

“…10 They also reported that GPRAdeficient mice showed the same allergic airway inflammation responses as the wild-type mice after ovalbumin challenge followed by aerosols of antigen exposure. 10 SNPs in GPRA have been associated with asthma and atopy susceptibility in Caucasians and Asians. However, findings are inconsistent across populations.…”

Section: Discussionmentioning

confidence: 91%

Lack of association between genetic variation in G-protein-coupled receptor for asthma susceptibility and childhood asthma and atopy

Romieu

Sienra-Monge

et al. 2008

Genes Immun

View full text Add to dashboard Cite

G-protein-coupled receptor for asthma susceptibility (GPRA or GPR154) was identified as an asthma and atopy candidate gene by positional cloning. Some subsequent studies suggest associations of GPRA single nucleotide polymorphisms (SNPs) and haplotypes with asthma or atopy susceptibility. However, the associated SNPs or haplotypes vary among studies. The role of GPRA genetic variation in asthma and atopy remains unsolved. Published data on GRPA variants and asthma come exclusively from Caucasian and Asian populations. We examined whether GPRA SNPs and haplotypes are associated with asthma and atopy in a Mexican population. We genotyped and analyzed 27 GPRA SNPs in 589 nuclear families consisting of asthmatic children aged 4-17 years of age and their parents in Mexico City. Atopy was determined by skin prick tests to 25 aeroallergens. The 27 SNPs examined provided excellent coverage of the GPRA gene. GPRA SNPs and haplotypes were not associated with childhood asthma and the degree of atopy to aeroallergens in a Mexican population. Our review of studies of GPRA variants in relation to asthma phenotypes shows considerable heterogeneity. Accordingly, our results suggest that GPRA variants are not an important contributor to childhood asthma and atopy susceptibility in a Mexican population.

show abstract

“…NPSR Ile107 shows a 5-to 10-fold increased agonist sensitivity compared with NPSR Asn107 when measuring second messenger responses, although binding affinity for the natural agonist NPS is unchanged at both receptor isoforms (Reinscheid et al, 2005). This polymorphism had been originally associated with an increased risk of asthma and other allergic diseases (Laitinen et al, 2004), but the role of NPSR in airway function is currently unclear (Allen et al, 2006). We have recently found evidence for a gender-specific association of the NPSR N107I polymorphism with panic disorder , and a genome-wide screen for markers of sleep behavior and circadian phenotypes identified the NPSR Ile107 polymorphism strongly associated with mean bedtime in a random population cohort (Gottlieb et al, 2007).…”

mentioning

confidence: 99%

Synthesis and Pharmacological in Vitro and in Vivo Profile of 3-Oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic Acid 4-Fluoro-benzylamide (SHA 68), a Selective Antagonist of the Neuropeptide S Receptor

Okamura

Habay²,

Zeng³

et al. 2008

J Pharmacol Exp Ther

114

151

View full text Add to dashboard Cite

Neuropeptide S (NPS) has been shown to modulate arousal, sleep wakefulness, anxiety-like behavior, and feeding after central administration of the peptide agonist to mice or rats. We report here the chemical synthesis and pharmacological characterization of SHA 66 (3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid benzylamide) and SHA 68 (3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide), two closely related bicyclic piperazines with antagonistic properties at the NPS receptor (NPSR). The compounds block NPS-induced Ca 2ϩ mobilization, and SHA 68 shows displaceable binding to NPSR in the nanomolar range. The antagonistic activity of SHA 68 seems to be specific because it does not affect signaling at 14 unrelated G protein-coupled receptors. Analysis of pharmacokinetic parameters of SHA 68 demonstrates that the compound reaches pharmacologically relevant levels in plasma and brain after i.p. administration. Furthermore, peripheral administration of SHA 68 in mice (50 mg/kg i.p.) is able to antagonize NPSinduced horizontal and vertical activity as well as stereotypic behavior. Therefore, SHA 68 could be a useful tool to characterize physiological functions and pharmacological parameters of the NPS system in vitro and in vivo.Neuropeptide S (NPS) and its receptor, NPSR, are a recently identified transmitter system that modulates a number of brain functions . NPS is a small peptide of 20 amino acids that occurs in all tetrapod vertebrates but is absent from fish (Reinscheid, 2007). Activation of NPSR produces transient increases in intracellular Ca 2ϩ and cAMP and thus increases cellular excitability (Reinscheid et al., 2005). Expression of NPS precursors and receptors is found in specific brain areas that have been associated with arousal, emotional processing, energy, and hormonal homeostasis, as well as learning and memory (Xu et al., 2004(Xu et al., , 2007. In the rat, NPS precursor transcripts are expressed in only a few brainstem structures; in particular, in a previously uncharacterized nucleus situated between the noradrenergic locus coeruleus and Barrington's nucleus. Besides the pericoerulear region, NPS mRNA is only found in the lateral parabrachial nucleus and the principle sensory 5 nucleus of the rat brainstem. A few scattered cells expressing NPS precursor transcripts are also detected in the amygdala and hypothalamus. In the brainstem, the majority of NPSexpressing neurons coexpress other excitatory transmitters, such as glutamate, acetylcholine, or corticotropin-releasing factor (Xu et al., 2007). NPSR mRNA is found at high levels in hypothalamus, thalamus, amygdala, various cortical regions, and the parahippocampal formation. Central administration of NPS was shown to produce profound arousal that is independent of novelty (Xu et al., 2004).

show abstract

Expression and function of NPSR1/GPRA in the lung before and after induction of asthma-like disease

Cited by 60 publications

References 38 publications

Role of Human Hypoxanthine Guanine Phosphoribosyltransferase in Activation of the Antiviral Agent T-705 (Favipiravir)

Role of Human Hypoxanthine Guanine Phosphoribosyltransferase in Activation of the Antiviral Agent T-705 (Favipiravir)

Lack of association between genetic variation in G-protein-coupled receptor for asthma susceptibility and childhood asthma and atopy

Synthesis and Pharmacological in Vitro and in Vivo Profile of 3-Oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic Acid 4-Fluoro-benzylamide (SHA 68), a Selective Antagonist of the Neuropeptide S Receptor

Contact Info

Product

Resources

About