title: Mechanisms of CO2/H+ Sensitivity of Astrocytes.
abstract: Ventral regions of the medulla oblongata of the brainstem are populated by astrocytes sensitive to physiological changes in PCO2/[H+]. These astrocytes respond to decreases in pH with elevations in intracellular Ca2+and facilitated exocytosis of ATP-containing vesicles. Released ATP propagates Ca2+excitation among neighboring astrocytes and activates neurons of the brainstem respiratory network triggering adaptive increases in breathing. The mechanisms linking increases in extracellular and/or intracellular PCO2/[H+] with Ca2+responses in chemosensitive astrocytes remain unknown. Fluorescent imaging of changes in [Na+]iand/or [Ca2+]iin individual astrocytes was performed in organotypic brainstem slice cultures and acute brainstem slices of adult rats. It was found that astroglial [Ca2+]iresponses triggered by decreases in pH are preceded by Na+entry, markedly reduced by inhibition of Na+/HCO3-cotransport (NBC) or Na+/Ca2+exchange (NCX), and abolished in Na+-free medium or by combined NBC/NCX blockade. Acidification-induced [Ca2+]iresponses were also dramatically reduced in brainstem astrocytes of mice deficient in the electrogenic Na+/HCO3-cotransporter NBCe1. Sensitivity of astrocytes to changes in pH was not affected by inhibition of Na+/H+exchange or blockade of phospholipase C. These results suggest that in pH-sensitive astrocytes, acidification activates NBCe1, which brings Na+inside the cell. Raising [Na+]iactivates NCX to operate in a reverse mode, leading to Ca2+entry followed by activation of downstream signaling pathways. Coupled NBC and NCX activities are, therefore, suggested to be responsible for functional CO2/H+sensitivity of astrocytes that contribute to homeostatic regulation of brain parenchymal pH and control of breathing.
  
  
  
  Brainstem astrocytes detect physiological changes in pH, activate neurons of the neighboring respiratory network, and contribute to the development of adaptive respiratory responses to the increases in the level of blood and brain PCO2/[H+]. The mechanisms underlying astroglial pH sensitivity remained unknown and here we show that in brainstem astrocytes acidification activates Na+/HCO3-cotransport, which brings Na+inside the cell. Raising [Na+]iactivates the Na+/Ca2+exchanger to operate in a reverse mode leading to Ca2+entry. This identifies a plausible mechanism of functional CO2/H+sensitivity of brainstem astrocytes, which play an important role in homeostatic regulation of brain pH and control of breathing.
authors: Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom.|Institute of Cell Biophysics, Russian Academy of Sciences, 142290 Pushchino, Russia.
authors: Egor
authors: E
authors: Turovsky
authors: Abteilung für Allgemeine Zoologie, Fachbereich Biologie, University of Kaiserslautern, D 67663 Kaiserslautern, Germany.
authors: Shefeeq M
authors: SM
authors: Theparambil
authors: Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom.
authors: Vitaliy
authors: 0000-0001-9543-9259
authors: V
authors: Kasymov
authors: Abteilung für Allgemeine Zoologie, Fachbereich Biologie, University of Kaiserslautern, D 67663 Kaiserslautern, Germany.
authors: Joachim W
authors: JW
authors: Deitmer
authors: William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
authors: Ana Gutierrez
authors: 0000-0003-1240-4654
authors: AG
authors: Del Arroyo
authors: William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
authors: Gareth L
authors: GL
authors: Ackland
authors: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona 85004, and.
authors: Jason J
authors: JJ
authors: Corneveaux
authors: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona 85004, and.
authors: April N
authors: AN
authors: Allen
authors: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona 85004, and.
authors: Matthew J
authors: MJ
authors: Huentelman
authors: School of Physiology & Pharmacology, University of Bristol, Bristol BS8 1TH, United Kingdom.
authors: Sergey
authors: S
authors: Kasparov
authors: Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom.
authors: Nephtali
authors: N
authors: Marina
authors: Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom, a.gourine@ucl.ac.uk.
authors: Alexander V
authors: AV
authors: Gourine
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001639:Bicarbonates / Q000378:metabolism; D020013:Calcium Signaling; D002245:Carbon Dioxide / Q000494:pharmacology*; D005089:Exocytosis; D006859:Hydrogen / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D012119:Respiration; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D012964:Sodium / Q000378:metabolism; D027982:Sodium-Bicarbonate Symporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001639:Bicarbonates; C422004:Slc4a4 protein, rat; D027982:Sodium-Bicarbonate Symporters; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; D002245:Carbon Dioxide; D006859:Hydrogen; D000255:Adenosine Triphosphate; D012964:Sodium
keywords: acidosis; brainstem; breathing; chemosensitivity; hypercapnia; respiration