title: A Novel Mechanism of pH Buffering in C. elegans Glia: Bicarbonate Transport via the Voltage-Gated ClC Cl- Channel CLH-1.
abstract: An important function of glia is the maintenance of the ionic composition and pH of the synaptic microenvironment. In terms of pH regulation, HCO3 (-) buffering has been shown to be important in both glia and neurons. Here, we used in vivo fluorescent pH imaging and RNA sequencing of the amphid sheath glia of Caenorhabditis elegans to reveal a novel mechanism of cellular HCO3 (-) uptake. While the classical mechanism of HCO3 (-) uptake involves Na(+)/HCO3 (-) cotransporters, here we demonstrate that the C. elegans ClC Cl(-) channel CLH-1 is highly permeable to HCO3 (-) and mediates HCO3 (-) uptake into amphid sheath glia. CLH-1 has homology and electrophysiological properties similar to the mammalian ClC-2 Cl(-) channel. Our data suggest that, in addition to maintaining synaptic Cl(-) concentration, these channels may also be involved in maintenance of synaptic pH via HCO3 (-) flux. These findings provide an exciting new facet of study regarding how pH is regulated in the brain.
  
  
  CONCLUSIONS
  Maintenance of pH is essential for the physiological function of the nervous system. HCO3 (-) is crucial for pH regulation and is transported into the cell via ion transporters, including ion channels, the molecular identity of which remains unclear. In this manuscript, we describe our discovery that the C. elegans amphid sheath glia regulate intracellular pH via HCO3 (-) flux through the voltage-gated ClC channel CLH-1. This represents a novel function for ClC channels, which has implications for their possible role in mammalian glial pH regulation. This discovery may also provide a novel therapeutic target for pathologic conditions, such as ischemic stroke where acidosis leads to widespread death of glia and subsequently neurons.
authors.affiliation: Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, Florida 33136.
authors.forename: Jeff
authors.initials: J
authors.lastname: Grant
authors.affiliation: Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, Florida 33136.
authors.forename: Cristina
authors.initials: C
authors.lastname: Matthewman
authors.affiliation: Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, Florida 33136 lbianchi@med.miami.edu.
authors.forename: Laura
authors.initials: L
authors.lastname: Bianchi
mesh_terms: D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D001693:Biological Transport, Active / Q000502:physiology; D002021:Buffers; D017173:Caenorhabditis elegans / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D018118:Chloride Channels / Q000378:metabolism*; D055724:Electrophysiological Phenomena / Q000235:genetics / Q000502:physiology; D015870:Gene Expression; D017930:Genes, Reporter / Q000235:genetics; D006863:Hydrogen-Ion Concentration; D009457:Neuroglia / Q000378:metabolism*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D013569:Synapses / Q000378:metabolism
chemical_list: D001639:Bicarbonates; D002021:Buffers; D029742:Caenorhabditis elegans Proteins; D018118:Chloride Channels; C402825:clh-1 protein, C elegans; D012313:RNA
keywords: C. elegans; RNA sequencing; bicarbonate; chloride channels; glia; pH