Proton Fall or Bicarbonate Rise

Abstract

Glycolysis is the primary step for major energy production in the cell. There is strong evidence suggesting that glucose consumption and rate of glycolysis are highly modulated by cytosolic pH The high energy requirement of the mammalian brain is primarily fueled by the degradation of blood-derived glucose. Astrocytes, the major glial cells in the brain, take up a large portion of blood glucose, and by aerobic glycolysis, they preferably produce more lactate (1, 2). Accumulating evidence suggests that astrocytes metabolically support neurons by releasing lactate, which then could be taken up by neighboring neurons (3, 4). Therefore, glucose metabolism in astrocytes was proposed to be modulated by various means of signals presumably originating from neurons (5, 6). It is well documented that astrocytes respond to neuronal activity with an intracellular alkalinization (7-9). Recently, it was shown that the glycolytic rate in astrocytes can be significantly enhanced by an alkaline pH i shift derived from extracellular K ϩ -induced membrane depolarization enhancing bicarbonate uptake via the electrogenic sodium bicarbonate cotransporter NBCe1 (10), which is highly expressed in mouse cortical astrocytes (11). In fact, cytoplasmic pH is well known to be a potential regulator of glucose metabolism, particularly the glycolytic rate, in various cell types (12)(13)(14)(15) ResultsWe have approached the question whether glucose consumption and glycolysis are stimulated by a fall in [H Ϫ transport into and out of astrocytes, we employed a genetic mouse model with a deletion in the gene for the electrogenic sodium bicarbonate cotransporter NBCe1 (SLC4A4) (21), which is highly expressed in mouse cortical astrocytes (11,22

Functional expression of electrogenic sodium bicarbonate cotransporter 1 (NBCe1) in mouse cortical astrocytes is dependent on S255‐257 and regulated by mTOR

“…Previous studies have shown NBCe1-dependent bicarbonate sensing and regulation of its activity during hypocapnic alkalosis and acute intracellular alkalosis in cortical astrocytes (Theparambil et al, , 2017Theparambil, Weber, Schmälzle, Ruminot, & Deitmer, 2016).…”

Bicarbonate alters cellular responses in respiration assays

“…These conditions necessitate bicarbonate-free media to circumvent alkalinisation. Although other buffering agents such as HEPES stabilise experimental pH, bicarbonate restriction could have a dramatic effect on cellular metabolism since bicarbonate acts as a nutrient, alters kinase signalling [6], and permits intracellular pH fluctuations [7]. …”

“…Second, bicarbonate alters cellular signalling responses, for example improving insulin sensitivity [6]. Third, it permits pH fluctuations in the cytosol, which can regulate metabolism (e.g., glycolysis [7]). Consequently, we assessed the potential for including bicarbonate in bioenergetic experiments.…”

TGF‐β signaling directly regulates transcription and functional expression of the electrogenic sodium bicarbonate cotransporter 1, NBCe1 (SLC4A4), via Smad4 in mouse astrocytes

“…Whereas neuronal firing leads to depolarization‐induced alkalinisation in astrocytes via activation of NBCe1, NBCe1 reverses during intracellular alkali load, thereby acting as an acid loader (Theparambil & Deitmer, 2015). NBCe1 plays also a crucial role in neuron‐glial metabolic coupling (Ruminot et al, 2011; Theparambil, Weber, Schmälzle, Ruminot, & Deitmer, 2016) and might also represent a molecular component of neuron‐astrocyte communication (Salameh, Hubner, & Boron, 2017). Changes in expression and function of NBCe1 have been observed in different in vitro (Yao et al, 2016) and in vivo models (Jung, Choi, & Kwon, 2007; Sohn et al, 2011) of ischemia and in seizures (Kang et al, 2002).…”