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METABOLIC ACIDOSIS AND THE DIVERSE ROLES OF THE Cl/HCO3 EXCHANGER (AE3) IN INTRACELLULAR pH HOMEOSTASIS
Salameh, Ahlam Ibrahim

2016, Doctor of Philosophy, Case Western Reserve University, Physiology and Biophysics.
In this dissertation, I examine the effects of extracellular metabolic acidosis (MAc)—a decrease in extracellular pH (pHo) caused by a decrease in [HCO3]o at fixed [CO2]o—on the intracellular pH (pHi) physiology of hippocampal neurons (HCN) and their adjacent astrocytes (HCA). It has been speculated that MAc lowers pHi because it inhibits acid extruders (proteins that transport acid equivalents out of the cytoplasm) or stimulates acid loaders (proteins that transport acid equivalents into the cytoplasm), mediated by the decrease in pHo, [HCO3]o or [CO3=]o. However, evidence supporting this hypothesis is indirect. In this dissertation, I directly investigate pHi trajectories in response to not just one, but twin MAc pulses in ten different cell types including HCN and HCA. The study reveals that although the general trend is for pHi to decrease, the extent of this decrease differs substantially among—and less so within—cell types. Furthermore, I find that the extent of the response to a second MAc is sometimes bigger than, sometimes similar to, and sometimes smaller than the response to the first MAc. After characterizing the general pHi trends in a wide range of cell types, I tested the contributions of an acid loader called the anion exchanger 3 (AE3) in shaping pHi profile in HCN and HCA in response to MAc. AE3 is expressed in neurons but not astrocytes and contributes to pHi regulation by facilitating the exchange of extracellular Cl- for intracellular HCO3. Using cells cultured from wild-type (WT) and AE3 knock-out (AE3-/-) mice, I find that the presence of AE3 speeds the rate of acidification in HCN recovering from intracellular alkali load or experiencing extracellular MAc. Additionally, I find that the presence of AE3 paradoxically enhances acid extrusion in HCN. Unexpectedly, the presence of AE3 in HCN has many of the same effects on the pHi physiology of adjacent HCA—a novel example of neuron-astrocyte crosstalk. This dissertation concludes that MAc indeed stimulates the acid loader AE3 in HCN but that the contribution of AE3 to pHi physiology in the hippocampus is far broader than its obvious role as an acid loader.
Walter F. Boron, M.D., Ph.D. (Advisor)
William Schilling, Ph.D. (Committee Chair)
Thomas Egelhoff, Ph.D. (Committee Member)
Christopher Ford, Ph.D. (Committee Member)
Kingman Strohl, M.D. (Committee Member)
Thomas Dick, Ph.D. (Committee Member)
232 p.

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Salameh, A. (2016). METABOLIC ACIDOSIS AND THE DIVERSE ROLES OF THE Cl/HCO3 EXCHANGER (AE3) IN INTRACELLULAR pH HOMEOSTASIS. (Electronic Thesis or Dissertation). Retrieved from https://etd.ohiolink.edu/

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Salameh, Ahlam. "METABOLIC ACIDOSIS AND THE DIVERSE ROLES OF THE Cl/HCO3 EXCHANGER (AE3) IN INTRACELLULAR pH HOMEOSTASIS." Electronic Thesis or Dissertation. Case Western Reserve University, 2016. OhioLINK Electronic Theses and Dissertations Center. 11 Dec 2017.

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Salameh, Ahlam "METABOLIC ACIDOSIS AND THE DIVERSE ROLES OF THE Cl/HCO3 EXCHANGER (AE3) IN INTRACELLULAR pH HOMEOSTASIS." Electronic Thesis or Dissertation. Case Western Reserve University, 2016. https://etd.ohiolink.edu/

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