Coupling hippocampal neurogenesis to brain ph through proneurogenic small molecules that regulate proton sensing G protein-coupled receptors

Jay W. Schneider, Sean C. Goetsch, Xiuyu Leng, Sara M. Ludwig, Jamie L. Russell, Cui Ping Yang, Qing Jun Zhang

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Acidosis, a critical aspect of central nervous system (CNS) pathophysiology and a metabolic corollary of the hypoxic stem cell niche, could be an expedient trigger for hippocampal neurogenesis and brain repair. We recently tracked the function of our isoxazole stem cell-modulator small molecules (Isx) through a chemical biology-target discovery strategy to GPR68, a proton (pH) sensing G protein-coupled receptor with no known function in brain. Isx and GPR68 coregulated neuronal target genes such as Bex1 (brain-enriched X-linked protein-1) in hippocampal neural progenitors (HCN cells), which further amplified GPR68 signaling by producing metabolic acid in response to Isx. To evaluate this proneurogenic small molecule/proton signaling circuit in vivo, we explored GPR68 and BEX1 expression in brain and probed brain function with Isx. We localized proton-sensing GPR68 to radial processes of hippocampal type 1 neural stem cells (NSCs) and, conversely, localized BEX1 to neurons. At the transcriptome level, Isx demonstrated unrivaled proneurogenic activity in primary hippocampal NSC cultures. In vivo, Isx pharmacologically targeted type 1 NSCs, promoting neurogenesis in young mice, depleting the progenitor pool without adversely affecting hippocampal learning and memory function. After traumatic brain injury, cerebral cortical astrocytes abundantly expressed GPR68, suggesting an additional role for proton-GPCR signaling in reactive astrogliosis. Thus, probing a novel proneurogenic synthetic small molecules mechanism-of-action, candidate target, and pharmacological activity, we identified a new GPR68 regulatory pathway for integrating neural stem and astroglial cell functions with brain pH.

Original languageEnglish (US)
Pages (from-to)557-568
Number of pages12
JournalACS Chemical Neuroscience
Volume3
Issue number7
DOIs
StatePublished - Jul 18 2012

Fingerprint

Neurogenesis
G-Protein-Coupled Receptors
Protons
Brain
Neural Stem Cells
Stem cells
Molecules
Stem Cells
Stem Cell Niche
Isoxazoles
Acidosis
Transcriptome
Astrocytes
Neurology
Cell culture
Modulators
Central Nervous System
Neurons
Cell Culture Techniques
Learning

Keywords

  • acidosis
  • G protein-coupled receptors
  • hippocampal neurogenesis
  • Small molecules
  • traumatic brain injury

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Physiology
  • Cognitive Neuroscience

Cite this

Coupling hippocampal neurogenesis to brain ph through proneurogenic small molecules that regulate proton sensing G protein-coupled receptors. / Schneider, Jay W.; Goetsch, Sean C.; Leng, Xiuyu; Ludwig, Sara M.; Russell, Jamie L.; Yang, Cui Ping; Zhang, Qing Jun.

In: ACS Chemical Neuroscience, Vol. 3, No. 7, 18.07.2012, p. 557-568.

Research output: Contribution to journalArticle

Schneider, Jay W. ; Goetsch, Sean C. ; Leng, Xiuyu ; Ludwig, Sara M. ; Russell, Jamie L. ; Yang, Cui Ping ; Zhang, Qing Jun. / Coupling hippocampal neurogenesis to brain ph through proneurogenic small molecules that regulate proton sensing G protein-coupled receptors. In: ACS Chemical Neuroscience. 2012 ; Vol. 3, No. 7. pp. 557-568.
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