title: Regulation of neuronal pH by the metabotropic Zn(2+)-sensing Gq-coupled receptor, mZnR/GPR39.
abstract: Synaptically released Zn(2+) acts as a neurotransmitter, in part, by activating the postsynaptic metabotropic Zn(2+)-sensing Gq protein-coupled receptor (mZnR/GPR39). In previous work using epithelial cells, we described crosstalk between Zn(2+) 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 Zn(2+) 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, Zn(2+)-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 Zn(2+)-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.
authors.affiliation: Department of Physiology and Cell Biology and The Zlotowski Center of Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Thibault
authors.initials: T
authors.lastname: Ganay
authors.affiliation: Department of Physiology and Cell Biology and The Zlotowski Center of Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Hila
authors.initials: H
authors.lastname: Asraf
authors.affiliation: Department of Physiology and Cell Biology and The Zlotowski Center of Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|Department of Neurobiology and Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Elias
authors.initials: E
authors.lastname: Aizenman
authors.affiliation: Department of Physiology and Cell Biology and The Zlotowski Center of Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Milos
authors.initials: M
authors.lastname: Bogdanovic
authors.affiliation: Department of Physiology and Cell Biology and The Zlotowski Center of Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Israel
authors.initials: I
authors.lastname: Sekler
authors.affiliation: Department of Physiology and Cell Biology and The Zlotowski Center of Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Hershfinkel
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*; D015032:Zinc / Q000378:metabolism*
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; C512928:GPR39 protein, mouse; D009570:Nitriles; D043562:Receptors, G-Protein-Coupled; D017923:Sodium-Hydrogen Exchangers; C113580:U 0126; D000255:Adenosine Triphosphate; D015032:Zinc
keywords: NHE; acidosis; mZnR/GPR39; pH; zinc; zinc sensing receptor