Pharmacology of neuropeptide S in mice: therapeutic relevance to anxiety disorders

Leonard, Sarah K.; Dwyer, Jason M.; Rizzo, Stacey J. Sukoff; Platt, Brian J.; Logue, Sheree F.; Neal, Sarah J.; Malberg, Jessica E.; Beyer, Chad E.; Schechter, Lee E.; Rosenzweig‐Lipson, Sharon; Ring, Robert H.

doi:10.1007/s00213-008-1080-4

Cited by 130 publications

(136 citation statements)

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“…This bias provided clear evidence that the hNPS-(1-10)-induced ERK1/2 phosphorylation had been attenuated by the G␣ q inhibitor UBO-QIC but not by the PKA inhibitor H89. Binding analysis using fluorescence-labeled NPS showed a similar activity in binding with the NPS receptor between WT NPS and NPS- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). These data strongly suggest that the fragment hNPS-(1-10) activates signaling biased toward the G␣ q -coupled cascade over G␣ s -dependent cascade through the NPS receptor.…”

Section: Discussionmentioning

confidence: 66%

“…These include the thalamus, hypothalamus, amygdala, and cortical areas (1,4,5). Upon central administration in rodents, NPS has been found to exert a variety of biological effects, including reduction of anxiety-related behavior (1,6,7), increase of locomotor activity (6,8,9), stimulation of wakefulness (1,6), inhibition of food intake (9,10), and enhancement of memory formation (11). Recent studies have also reported its involvement in the suppression of alcohol consumption (12,13) and in the extinction of contextual conditioned fear responses (14,15).…”

mentioning

confidence: 99%

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Human Neuropeptide S Receptor Is Activated via a Gαq Protein-biased Signaling Cascade by a Human Neuropeptide S Analog Lacking the C-terminal 10 Residues

Yuan

Lü

et al. 2016

Journal of Biological Chemistry

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Human neuropeptide S (NPS) and its cognate receptor regulate important biological functions in the brain and have emerged as a future therapeutic target for treatment of a variety of neurological and psychiatric diseases. The human NPS (hNPS) receptor has been shown to dually couple to G␣ s -and G␣ q -dependent signaling pathways. The human NPS analog hNPS-(1-10), lacking 10 residues from the C terminus, has been shown to stimulate Ca 2؉ mobilization in a manner comparable with full-length hNPS in vitro but seems to fail to induce biological activity in vivo. Here, results derived from a number of cellbased functional assays, including intracellular cAMP-response element (CRE)-driven luciferase activity, Ca 2؉ mobilization, and ERK1/2 phosphorylation, show that hNPS-(1-10) preferentially activates G␣ q -dependent Ca 2؉ mobilization while exhibiting less activity in triggering G␣ s -dependent CRE-driven luciferase activity. We further demonstrate that both G␣ q -and G␣ s -coupled signaling pathways contribute to full-length hNPS-mediated activation of ERK1/2, whereas hNPS-(1-10)-promoted ERK1/2 activation is completely inhibited by the G␣ q inhibitor UBO-QIC but not by the PKA inhibitor H89. Moreover, the results of Ala-scanning mutagenesis of hNPS-(1-13) indicated that residues Lys 11 and Lys 12 are structurally crucial for the hNPS receptor to couple to G␣ s -dependent signaling. In conclusion, our findings demonstrate that hNPS-(1-10) is a biased agonist favoring G␣ q -dependent signaling. It may represent a valuable chemical probe for further investigation of the therapeutic potential of human NPS receptor-directed signaling in vivo.

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Section: Discussionmentioning

confidence: 66%

mentioning

confidence: 99%

Human Neuropeptide S Receptor Is Activated via a Gαq Protein-biased Signaling Cascade by a Human Neuropeptide S Analog Lacking the C-terminal 10 Residues

Yuan

Lü

et al. 2016

Journal of Biological Chemistry

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“…After having ascertained that intranasally administered NPS reaches its target cells, we established its anxiolytic effects reported in intracerebral administration studies (Xu et al, 2004;Leonard et al, 2008) for this transnasal delivery method. In order to define the most efficient treatment dose, we delivered three different doses of NPS (7, 14, and 28 nmol) intranasally to C57BL/6N mice, a mouse strain reported to show reduced anxiety after ICV administration of NPS (Xu et al, 2004;Jüngling et al, 2008;Fendt et al, 2010).…”

Section: Intranasally Administered Nps Exerts Strong Anxiolytic Effecmentioning

confidence: 99%

“…The novel neuropeptide S (NPS) has been shown to elicit strong anxiolytic effects in rodents upon intracerebral injection (Leonard et al, 2008;Xu et al, 2004). NPS treatment facilitates fear extinction in mice and reduces fear memory retrieval after extinction training (Jüngling et al, 2008), thus becoming interesting especially for posttraumatic stress disorder (PTSD) treatment.…”

Section: Introductionmentioning

confidence: 99%

“…NPS interacts with many neurotransmitter systems in the brain, including the glutamatergic network (Han et al, 2009;Raiteri et al, 2009;Si et al, 2010;Okamura et al, 2010), which is involved in the pathology of disorders such as PTSD (Rossi et al, 2009;Ravindran and Stein, 2009). The anxiolytic properties of NPS are not mediated by the benzodiazepine-binding site of the GABA A receptor (Leonard et al, 2008), thus suggesting that its administration would not cause benzodiazepine-like side effects. However, the intracerebral NPS administration techniques employed in animal experiments reported so far are hardly transferable to human clinical use.…”

Section: Introductionmentioning

confidence: 99%

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Intranasally Administered Neuropeptide S (NPS) Exerts Anxiolytic Effects Following Internalization Into NPS Receptor-Expressing Neurons

Ionescu

Dine

Yen

et al. 2012

Neuropsychopharmacol

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Experiments in rodents revealed neuropeptide S (NPS) to constitute a potential novel treatment option for anxiety diseases such as panic and post-traumatic stress disorder. However, both its cerebral target sites and the molecular underpinnings of NPS-mediated effects still remain elusive. By administration of fluorophore-conjugated NPS, we pinpointed NPS target neurons in distinct regions throughout the entire brain. We demonstrated their functional relevance in the hippocampus. In the CA1 region, NPS modulates synaptic transmission and plasticity. NPS is taken up into NPS receptor-expressing neurons by internalization of the receptor-ligand complex as we confirmed by subsequent cell culture studies. Furthermore, we tracked internalization of intranasally applied NPS at the single-neuron level and additionally demonstrate that it is delivered into the mouse brain without losing its anxiolytic properties. Finally, we show that NPS differentially modulates the expression of proteins of the glutamatergic system involved inter alia in synaptic plasticity. These results not only enlighten the path of NPS in the brain, but also establish a non-invasive method for NPS administration in mice, thus strongly encouraging translation into a novel therapeutic approach for pathological anxiety in humans.

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Molecular fingerprint of neuropeptide s‐producing neurons in the mouse brain

Liu

Zeng

Zhou

et al. 2011

J of Comparative Neurology

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Neuropeptide S (NPS) has been associated with a number of complex brain functions, including anxiety-like behaviors, arousal, sleep-wakefulness regulation, drug-seeking behaviors, and learning and memory. In order to better understand how NPS influences these functions in a neuronal network context, it is critical to identify transmitter systems that control NPS release and transmitters that are co-released with NPS. For this purpose, we generated several lines of transgenic mice that express enhanced green-fluorescent protein (EGFP) under control of the endogenous NPS precursor promoter. NPS/EGFP-transgenic mice show anatomically correct and overlapping expression of both NPS and EGFP. A total number of ∼500 NPS/EGFP-positive neurons are present in the mouse brain, located in the pericoerulear region and the Kölliker-Fuse nucleus. NPS and transgene expression is first detectable around E14, indicating a potential role for NPS in brain development. EGFP-positive cells were harvested by laser-capture microdissection, and mRNA was extracted for expression profiling by using microarray analysis. NPS was found co-localized with galanin in the Kölliker-Fuse nucleus of the lateral parabrachial area. A dense network of orexin/hypocretin neuronal projections contacting pericoerulear NPS-producing neurons was observed by immunostaining. Expression of a distinct repertoire of metabotropic and ionotropic receptor genes was identified in both NPS neuronal clusters that will allow for detailed investigations of incoming neurotransmission, controlling neuronal activity of NPS-producing neurons. Stress-induced functional activation of NPS-producing neurons was detected by staining for the immediate-early gene c-fos, thus supporting earlier findings that NPS might be part of the brain stress response network.

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Pharmacology of neuropeptide S in mice: therapeutic relevance to anxiety disorders

Abstract: These data provide an important confirmation and expansion of the anxiolytic-like effects of NPS and implicate the NPS system as a novel target for anxiolytic drug discovery.

Cited by 130 publications

References 39 publications

Human Neuropeptide S Receptor Is Activated via a Gαq Protein-biased Signaling Cascade by a Human Neuropeptide S Analog Lacking the C-terminal 10 Residues

Human Neuropeptide S Receptor Is Activated via a Gαq Protein-biased Signaling Cascade by a Human Neuropeptide S Analog Lacking the C-terminal 10 Residues

Intranasally Administered Neuropeptide S (NPS) Exerts Anxiolytic Effects Following Internalization Into NPS Receptor-Expressing Neurons

Molecular fingerprint of neuropeptide s‐producing neurons in the mouse brain

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