PMID- 36555637
OWN - NLM
STAT- MEDLINE
DCOM- 20221226
LR  - 20221227
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 23
IP  - 24
DP  - 2022 Dec 15
TI  - Novel Small Molecule Positive Allosteric Modulator SPAM1 Triggers the Nuclear 
      Translocation of PAC1-R to Exert Neuroprotective Effects through 
      Neuron-Restrictive Silencer Factor.
LID - 10.3390/ijms232415996 [doi]
LID - 15996
AB  - 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(2)O(2)) 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.
FAU - Fan, Guangchun
AU  - Fan G
AUID- ORCID: 0000-0003-2475-298X
AD  - Department of Cell Biology, College of Life Science and Technology, Jinan 
      University, Guangzhou 510632, China.
FAU - Chen, Shang
AU  - Chen S
AD  - Department of Cell Biology, College of Life Science and Technology, Jinan 
      University, Guangzhou 510632, China.
FAU - Liang, Lili
AU  - Liang L
AD  - Department of Cell Biology, College of Life Science and Technology, Jinan 
      University, Guangzhou 510632, China.
FAU - Zhang, Huahua
AU  - Zhang H
AD  - Department of Medical Genetics, Guangdong Medical University, Dongguan 523808, 
      China.
FAU - Yu, Rongjie
AU  - Yu R
AD  - Department of Cell Biology, College of Life Science and Technology, Jinan 
      University, Guangzhou 510632, China.
AD  - Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou 510632, 
      China.
AD  - Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, 
      Guangzhou 510632, China.
AD  - National Engineering Research Center of Genetic Medicine, Guangzhou 510632, 
      China.
LA  - eng
GR  - No. 31100545, No. 31670848/National Natural Science Foundation of China/
GR  - No. 2016A030313087, No. 2022A1515011158/Natural Science Foundation of Guangdong 
      Province/
PT  - Journal Article
DEP - 20221215
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Pituitary Adenylate Cyclase-Activating Polypeptide)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (RE1-silencing transcription factor)
RN  - 0 (Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I)
RN  - BBX060AN9V (Hydrogen Peroxide)
SB  - IM
MH  - Cricetinae
MH  - Mice
MH  - Animals
MH  - *Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism
MH  - *Neuroprotective Agents/pharmacology
MH  - Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I/metabolism
MH  - Cricetulus
MH  - Hydrogen Peroxide
PMC - PMC9784932
OTO - NOTNLM
OT  - D-galactose (D-gal)
OT  - PAC1-R
OT  - SPAM1
OT  - huntingtin
OT  - neuron-restrictive silencer factor (NRSF)
OT  - neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP)
OT  - neuroprotective effect
OT  - positive allosteric modulator (PAM)
COIS- The authors have no conflict of interest to declare.
EDAT- 2022/12/24 06:00
MHDA- 2022/12/27 06:00
PMCR- 2022/12/15
CRDT- 2022/12/23 01:35
PHST- 2022/11/28 00:00 [received]
PHST- 2022/12/09 00:00 [revised]
PHST- 2022/12/10 00:00 [accepted]
PHST- 2022/12/23 01:35 [entrez]
PHST- 2022/12/24 06:00 [pubmed]
PHST- 2022/12/27 06:00 [medline]
PHST- 2022/12/15 00:00 [pmc-release]
AID - ijms232415996 [pii]
AID - ijms-23-15996 [pii]
AID - 10.3390/ijms232415996 [doi]
PST - epublish
SO  - Int J Mol Sci. 2022 Dec 15;23(24):15996. doi: 10.3390/ijms232415996.