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.
We show that the postsynaptic metabotropic Zn2+‐sensing Gq protein‐coupled receptor (mZnR/GPR39) activation induces up‐regulation of a major neuronal H+ extrusion pathway, the Na+/H+ exchanger (NHE), thereby enhancing neuronal recovery from intracellular acidification. Changes in extracellular pH (pHe), however, modulate neuronal mZnR/GPR39‐dependent signaling, resulting in reduced activity at pHe 8 or 6.5. This mechanism may serve to protect neurons from excessive decreases in pHe during acidosis. Hence, mZnR/GPR39 signaling provides a homeostatic adaptive process for regulation of intracellular and extracellular pH changes in the brain.