Affinity, potency, efficacy, and selectivity of neurokinin A analogs at human recombinant NK2 and NK1 receptors

Rupniak, N. M. J.; Perdonà, Elisabetta; Griffante, Cristiana; Cavallini, Palmina; Sava, Anna; Ricca, Daniel J.; Thor, Karl B.; Burgard, Edward C.; Corsi, Mauro

doi:10.1371/journal.pone.0205894

Cited by 14 publications

(6 citation statements)

References 29 publications

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“…4a, b). The high potency of SP (EC50 = 5.9 ± 0.4 nM) to increase [Ca 2+ ] c is consistent with activation of NK1R 19 .…”

Section: Resultssupporting

confidence: 73%

“…the long (TACR1l) and short (TACR1s) variants. The NK1R has a high affinity for SP (EC50 = 1 nM) and weakly binds NKA, while the NK2 receptor (NK2R) is principally activated by NKA but exhibits a low affinity for SP (EC50 = 100 nM) 18,19 . In human adrenals, RT-PCR analyses allowed detection of TACR1l and TACR1s mRNA whereas TACR2 mRNA levels were very low and TACR3 mRNA appeared undetectable ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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The neuropeptide substance P regulates aldosterone secretion in human adrenals

et al. 2020

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Aldosterone, produced by the adrenals and under the control of plasma angiotensin and potassium levels, regulates hydromineral homeostasis and blood pressure. Here we report that the neuropeptide substance P (SP) released by intraadrenal nerve fibres, stimulates aldosterone secretion via binding to neurokinin type 1 receptors (NK1R) expressed by aldosterone-producing adrenocortical cells. The action of SP is mediated by the extracellular signal-regulated kinase pathway and involves upregulation of steroidogenic enzymes. We also conducted a prospective proof-of-concept, double blind, placebo-controlled clinical trial aimed to investigate the impact of the NK1R antagonist aprepitant on aldosterone secretion in healthy male volunteers (EudraCT: 2008-003367-40, ClinicalTrial.gov: NCT00977223). Participants received during two 7-day treatment periods aprepitant (125 mg on the 1 st day and 80 mg during the following days) or placebo in a random order at a 2-week interval. The primary endpoint was plasma aldosterone levels during posture test. Secondary endpoints included basal aldosterone alterations, plasma aldosterone variation during metoclopramide and hypoglycaemia tests, and basal and stimulated alterations of renin, cortisol and ACTH during the three different stimulatory tests. The safety of the treatment was assessed on the basis of serum transaminase measurements on days 4 and 7. All pre-specified endpoints were achieved. Aprepitant decreases aldosterone production by around 30% but does not influence the aldosterone response to upright posture. These results indicate that the autonomic nervous system exerts a direct stimulatory tone on mineralocorticoid synthesis through SP, and thus plays a role in the maintenance of hydromineral homeostasis. This regulatory mechanism may be involved in aldosterone excess syndromes.

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“…4a, b). The high potency of SP (EC50 = 5.9 ± 0.4 nM) to increase [Ca 2+ ] c is consistent with activation of NK1R 19 .…”

Section: Resultssupporting

confidence: 73%

Section: Resultsmentioning

confidence: 99%

The neuropeptide substance P regulates aldosterone secretion in human adrenals

et al. 2020

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“…Furthermore, NPs and their receptors are implicated in the acquisition of oncogenic properties and the facilitation of bone marrow metastasis [14–18]. SP bind preferentially to the NK1 receptor (unlike NKA that can bind to both NK1 and NK2 receptors [19]). Concomitantly, CGRP bind to the G Protein-Coupled Receptor complex formed between calcitonin receptor-like receptor (CALCRL) and the receptor activity modifying protein (RAMP-1) for review see Barwell et al [20].…”

Section: Introductionmentioning

confidence: 99%

Neuropeptide-induced modulation of carcinogenesis in a metastatic breast cancer cell line (MDA-MB-231LUC+)

Gutiérrez

Boada

2018

Cancer Cell Int

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BackgroundMetastatic cancer to bone is well-known to produce extreme pain. It has been suggested that the magnitude of this perceived pain is associated with disease progression and poor prognosis. These data suggest a potential cross-talk between cancer cells and nociceptors that contribute not only to pain, but also to cancer aggressiveness although the underlying mechanisms are yet to be stablished.MethodsThe in vitro dose dependent effect of neuropeptides (NPs) (substance P [SP], calcitonin gene-related peptide and neurokinin A [NKA]) and/or its combination, on the migration and invasion of MDA-MB-231LUC+ were assessed by wound healing and collagen-based cell invasion assays, respectively. The effect of NPs on the expression of its receptors (SP [NK1] and neurokinin A receptors [NK2], CALCRL and RAMP1) and kininogen (high-molecular-weight kininogen) release to the cell culture supernatant of MDA-MB-231LUC+, were measured using western-blot analysis and an ELISA assay, respectively. Statistical significance was tested using one-way ANOVA, repeated measures ANOVA, or the paired t-test. Post-hoc testing was performed with correction for multiple comparisons as appropriate.ResultsOur data show that NPs strongly modify the chemokinetic capabilities of a cellular line commonly used as a model of metastatic cancer to bone (MDA-MB-231LUC+) and increased the expression of their receptors (NK1R, NK2R, RAMP1, and CALCRL) on these cells. Finally, we demonstrate that NPs also trigger the acute release of HMWK (Bradykinin precursor) by MDA-MB-231LUC+, a molecule with both tumorigenic and pro-nociceptive activity.ConclusionsBased on these observations we conclude that NPs exposure modulates this breast cancer cellular line aggressiveness by increasing its ability to migrate and invade new tissues. Furthermore, these results also support the pro nociceptive and cancer promoter role of the peripheral nervous system, during the initial stages of the disease.

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“…While the development of NK2 agonists has great potential for the treatment of voiding and defecatory dysfunction, there are also significant limitations due to their poor selectivity for NK2 receptors over NK1 receptors. Activation of NK1 by NKA and related analogs can cause significant unwanted effects including hypotension and emesis . Further studies are currently being conducted to evaluate NK2 agonists as a treatment option for patients with UAB that may afford these patients a rapid onset, yet short in duration, option for the control of micturition and/or defecation and reduced or eliminated the need for catheterization.…”

Section: Managementmentioning

confidence: 99%

Detrusor underactivity in women: A current understanding

Hartigan

Reynolds

Dmochowski

2019

Neurourology and Urodynamics

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Aims To examine the current understanding and management of detrusor underactivity (DUA) and underactive bladder (UAB) in women. Methods A review of the current literature was performed with a specific focus on new management strategies and treatment options for women with DUA and UAB. Results DUA has become an area of increased interest in recent years. Affecting up to 45% of older women undergoing urodynamic evaluation for non‐neurogenic lower urinary tract symptoms, DUA is common. There are a variety of possible etiologies including neurogenic or myogenic dysfunction. As there is currently no cure for DUA and no way to restore the ability of the detrusor muscle to contract, management of DUA in women is mostly focused on effective bladder drainage by urinary catheterization. Clean intermittent catheterization is the gold standard for bladder drainage however for a variety of reasons, women with DUA often are managed with indwelling urethral catheter or suprapubic tube. Medications, sacral neuromodulation, and the inFlow urinary prosthesis are also treatment alternatives or additions to catheterization. Novel therapies using stem cells and gene therapy are also under investigation for the treatment of DUA and UAB. Conclusions DUA is likely more prevalent than recognized and undertreated in women. It is vital that further research in treatment options beyond catheterization be developed for these patients to offer patients a variety of treatment options.

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Affinity, potency, efficacy, and selectivity of neurokinin A analogs at human recombinant NK2 and NK1 receptors

Cited by 14 publications

References 29 publications

The neuropeptide substance P regulates aldosterone secretion in human adrenals

The neuropeptide substance P regulates aldosterone secretion in human adrenals

Neuropeptide-induced modulation of carcinogenesis in a metastatic breast cancer cell line (MDA-MB-231LUC+)

Detrusor underactivity in women: A current understanding

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