Novel Small Molecule Positive Allosteric Modulator SPAM1 Triggers the Nuclear Translocation of PAC1-R to Exert Neuroprotective Effects through Neuron-Restrictive Silencer Factor
The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) exerts effective neuroprotective activity through its specific receptor, PAC1-R. We accidentally discovered that as a positive allosteric modulator (PAM) of PAC1-R, the small-molecule PAM (SPAM1) has a hydrazide-like structu...
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2022-12-01
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author | Guangchun Fan Shang Chen Lili Liang Huahua Zhang Rongjie Yu |
author_facet | Guangchun Fan Shang Chen Lili Liang Huahua Zhang Rongjie Yu |
author_sort | Guangchun Fan |
collection | DOAJ |
description | The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) exerts effective neuroprotective activity through its specific receptor, PAC1-R. We accidentally discovered that as a positive allosteric modulator (PAM) of PAC1-R, the small-molecule PAM (SPAM1) has a hydrazide-like structure, but different binding characteristics, from hydrazide for the N-terminal extracellular domain of PAC1-R (PAC1-R-EC1). SPAM1 had a significant neuroprotective effect against oxidative stress, both in a cell model treated with hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) and an aging mouse model induced by D-galactose (D-gal). SPAM1 was found to block the decrease in PACAP levels in brain tissues induced by D-gal and significantly induced the nuclear translocation of PAC1-R in PAC1R-CHO cells and mouse retinal ganglion cells. Nuclear PAC1-R was subjected to fragmentation and the nuclear 35 kDa, but not the 15 kDa fragments, of PAC1-R interacted with SP1 to upregulate the expression of Huntingtin (Htt), which then exerted a neuroprotective effect by attenuating the binding availability of the neuron-restrictive silencer factor (NRSF) to the neuron-restrictive silencer element (NRSE). This resulted in an upregulation of the expression of NRSF-related neuropeptides, including PACAP, the brain-derived neurotrophic factor (BDNF), tyrosine hydroxylase (TH), and synapsin-1 (SYN1). The novel mechanism reported in this study indicates that SPAM1 has potential use as a drug, as it exerts a neuroprotective effect by regulating NRSF. |
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spelling | doaj.art-6a79314332144a8883ae007cff0c49f82023-11-24T15:31:05ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-12-0123241599610.3390/ijms232415996Novel Small Molecule Positive Allosteric Modulator SPAM1 Triggers the Nuclear Translocation of PAC1-R to Exert Neuroprotective Effects through Neuron-Restrictive Silencer FactorGuangchun Fan0Shang Chen1Lili Liang2Huahua Zhang3Rongjie Yu4Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, ChinaDepartment of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, ChinaDepartment of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, ChinaDepartment of Medical Genetics, Guangdong Medical University, Dongguan 523808, ChinaDepartment of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, ChinaThe neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) exerts effective neuroprotective activity through its specific receptor, PAC1-R. We accidentally discovered that as a positive allosteric modulator (PAM) of PAC1-R, the small-molecule PAM (SPAM1) has a hydrazide-like structure, but different binding characteristics, from hydrazide for the N-terminal extracellular domain of PAC1-R (PAC1-R-EC1). SPAM1 had a significant neuroprotective effect against oxidative stress, both in a cell model treated with hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) and an aging mouse model induced by D-galactose (D-gal). SPAM1 was found to block the decrease in PACAP levels in brain tissues induced by D-gal and significantly induced the nuclear translocation of PAC1-R in PAC1R-CHO cells and mouse retinal ganglion cells. Nuclear PAC1-R was subjected to fragmentation and the nuclear 35 kDa, but not the 15 kDa fragments, of PAC1-R interacted with SP1 to upregulate the expression of Huntingtin (Htt), which then exerted a neuroprotective effect by attenuating the binding availability of the neuron-restrictive silencer factor (NRSF) to the neuron-restrictive silencer element (NRSE). This resulted in an upregulation of the expression of NRSF-related neuropeptides, including PACAP, the brain-derived neurotrophic factor (BDNF), tyrosine hydroxylase (TH), and synapsin-1 (SYN1). The novel mechanism reported in this study indicates that SPAM1 has potential use as a drug, as it exerts a neuroprotective effect by regulating NRSF.https://www.mdpi.com/1422-0067/23/24/15996neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP)PAC1-Rpositive allosteric modulator (PAM)SPAM1D-galactose (D-gal)huntingtin |
spellingShingle | Guangchun Fan Shang Chen Lili Liang Huahua Zhang Rongjie Yu Novel Small Molecule Positive Allosteric Modulator SPAM1 Triggers the Nuclear Translocation of PAC1-R to Exert Neuroprotective Effects through Neuron-Restrictive Silencer Factor International Journal of Molecular Sciences neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) PAC1-R positive allosteric modulator (PAM) SPAM1 D-galactose (D-gal) huntingtin |
title | Novel Small Molecule Positive Allosteric Modulator SPAM1 Triggers the Nuclear Translocation of PAC1-R to Exert Neuroprotective Effects through Neuron-Restrictive Silencer Factor |
title_full | Novel Small Molecule Positive Allosteric Modulator SPAM1 Triggers the Nuclear Translocation of PAC1-R to Exert Neuroprotective Effects through Neuron-Restrictive Silencer Factor |
title_fullStr | Novel Small Molecule Positive Allosteric Modulator SPAM1 Triggers the Nuclear Translocation of PAC1-R to Exert Neuroprotective Effects through Neuron-Restrictive Silencer Factor |
title_full_unstemmed | Novel Small Molecule Positive Allosteric Modulator SPAM1 Triggers the Nuclear Translocation of PAC1-R to Exert Neuroprotective Effects through Neuron-Restrictive Silencer Factor |
title_short | Novel Small Molecule Positive Allosteric Modulator SPAM1 Triggers the Nuclear Translocation of PAC1-R to Exert Neuroprotective Effects through Neuron-Restrictive Silencer Factor |
title_sort | novel small molecule positive allosteric modulator spam1 triggers the nuclear translocation of pac1 r to exert neuroprotective effects through neuron restrictive silencer factor |
topic | neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) PAC1-R positive allosteric modulator (PAM) SPAM1 D-galactose (D-gal) huntingtin |
url | https://www.mdpi.com/1422-0067/23/24/15996 |
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