Regulation of neuronal pH by the metabotropic Zn2+-sensing Gq-coupled receptor, mZnR/GPR39

Thibault Ganay, Hila Asraf, Elias Aizenman, Milos Bogdanovic, Israel Sekler, Michal Hershfinkel

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


Synaptically released Zn2+ acts as a neurotransmitter, in part, by activating the postsynaptic metabotropic Zn2+-sensing Gq protein-coupled receptor (mZnR/GPR39). In previous work using epithelial cells, we described crosstalk between Zn2+ signaling and changes in intracellular pH and/or extracellular pH (pHe). As pH changes accompany neuronal activity under physiological and pathological conditions, we tested whether Zn2+ signaling is involved in regulation of neuronal pH. Here, we report that up-regulation of a major H+ extrusion pathway, the Na+/H+ exchanger (NHE), is induced by mZnR/GPR39 activation in an extracellular-regulated kinase 1/2-dependent manner in hippocampal neurons in vitro. We also observed that changes in pHe can modulate neuronal mZnR/GPR39-dependent signaling, resulting in reduced activity at pHe 8 or 6.5. Similarly, Zn2+-dependent extracellular-regulated kinase 1/2 phosphorylation and up-regulation of NHE activity were absent at acidic pHe. Thus, our results suggest that when pHe is maintained within the physiological range, mZnR/GPR39 activation can up-regulate NHE-dependent recovery from intracellular acidification. During acidosis, as pHe drops, mZnR/GPR39-dependent NHE activation is inhibited, thereby attenuating further H+ extrusion. This mechanism may serve to protect neurons from excessive decreases in pHe. Thus, mZnR/GPR39 signaling provides a homeostatic adaptive process for regulation of intracellular and extracellular pH changes in the brain.

Original languageEnglish
Pages (from-to)897-907
Number of pages11
JournalJournal of Neurochemistry
Issue number5
StatePublished - 1 Dec 2015


  • NHE
  • acidosis
  • mZnR/GPR39
  • pH
  • zinc
  • zinc sensing receptor

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience


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