Bicarbonate transport in health and disease

Kumari, Aruna; Casey, Joseph R.

doi:10.1002/iub.1315

Cited by 79 publications

(91 citation statements)

References 277 publications

(329 reference statements)

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“…AE4 (Slc4a9) is not yet fully characterized. Initial cloning of the gene demonstrated Cl – transport function of the protein, although phylogenetically this isoform is much more closely related to the Na + -coupled HCO 3 – transporters (Alka and Casey, 2014; Ko et al, 2002). Recent evidence suggests that AE4 functions as a Na + -dependent Cl – /HCO 3 – transporter in salivary glands, making AE4 distinct in its transport profile (Pena-Munzenmayer et al, 2015).…”

Section: Acid–base Regulatory Mechanismsmentioning

confidence: 99%

Emerging roles of Na+/H+ exchangers in epilepsy and developmental brain disorders

Zhao

Carney

Falgoust

et al. 2016

Progress in Neurobiology

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Epilepsy is a common central nervous system (CNS) disease characterized by recurrent transient neurological events occurring due to abnormally excessive or synchronous neuronal activity in the brain. The CNS is affected by systemic acid–base disorders, and epileptic seizures are sensitive indicators of underlying imbalances in cellular pH regulation. Na+/H+ exchangers (NHEs) are a family of membrane transporter proteins actively involved in regulating intracellular and organellar pH by extruding H+ in exchange for Na+ influx. Altering NHE function significantly influences neuronal excitability and plays a role in epilepsy. This review gives an overview of pH regulatory mechanisms in the brain with a special focus on the NHE family and the relationship between epilepsy and dysfunction of NHE isoforms. We first discuss how cells translocate acids and bases across the membrane and establish pH homeostasis as a result of the concerted effort of enzymes and ion transporters. We focus on the specific roles of the NHE family by detailing how the loss of NHE1 in two NHE mutant mice results in enhanced neuronal excitability in these animals. Furthermore, we highlight new findings on the link between mutations of NHE6 and NHE9 and developmental brain disorders including epilepsy, autism, and attention deficit hyperactivity disorder (ADHD). These studies demonstrate the importance of NHE proteins in maintaining H+ homeostasis and their intricate roles in the regulation of neuronal function. A better understanding of the mechanisms underlying NHE1, 6, and 9 dysfunctions in epilepsy formation may advance the development of new epilepsy treatment strategies.

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Section: Acid–base Regulatory Mechanismsmentioning

confidence: 99%

Emerging roles of Na+/H+ exchangers in epilepsy and developmental brain disorders

Zhao

Carney

Falgoust

et al. 2016

Progress in Neurobiology

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“…Bicarbonate is necessary for several redox reactions [8–10], for mitochondrial metabolism [11] and acts as a co-transporter in membrane channels [11,12]. While CO 2 /bicarbonate is known to participate in redox metabolism [8,13], we were the first to show that the presence of bicarbonate increases protein oxidation under pathophysiological conditions [7].…”

Section: Introductionmentioning

confidence: 99%

Bicarbonate Increases Ischemia-Reperfusion Damage by Inhibiting Mitophagy

Queliconi

Kowaltowski

Gottlieb³

2016

PLoS ONE

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During an ischemic event, bicarbonate and CO2 concentration increase as a consequence of O2 consumption and lack of blood flow. This event is important as bicarbonate/CO2 is determinant for several redox and enzymatic reactions, in addition to pH regulation. Until now, most work done on the role of bicarbonate in ischemia-reperfusion injury focused on pH changes; although reperfusion solutions have a fixed pH, cardiac resuscitation protocols commonly employ bicarbonate to correct the profound acidosis associated with respiratory arrest. However, we previously showed that bicarbonate can increase tissue damage and protein oxidative damage independent of pH. Here we show the molecular basis of bicarbonate-induced reperfusion damage: the presence of bicarbonate selectively impairs mitophagy, with no detectable effect on autophagy, proteasome activity, reactive oxygen species production or protein oxidation. We also show that inhibition of autophagy reproduces the effects of bicarbonate in reperfusion injury, providing additional evidence in support of this mechanism. This phenomenon is especially important because bicarbonate is widely used in resuscitation protocols after cardiac arrest, and while effective as a buffer, may also contribute to myocardial injury.

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“…Most (> 90%) of the carbon dioxide inside and outside erythrocytes in blood is converted to anions HCO 3 − (the enzyme carbonic anhydrase accelerates this reaction) ( (55). The importance of this theme is supported by known publications (8,(56)(57)(58)(59)(60)(61). For example, it was reported (57) that in the case of hypoxia the amount of active CDB3 per erythrocyte of asphyxiated neonates was decreased in comparison with healthy newborns.…”

Section: Discussionmentioning

confidence: 95%

“…Binding of Ca 2+ with CDB3 is considered as the equilibrium reaction (7) due to its relatively high rate according to know literature data (34). The buffer reaction Scheme (5) is necessary to combine the transport Scheme (1)-(4) with the activation Scheme (6)- (8).…”

Section: Discussionmentioning

confidence: 99%

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Proposed Dynamics of CDB3 Activation in Human Erythrocytes by Nifedipine Studied with Scanning Flow Cytometry

et al. 2019

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Nifedipine is calcium channels and pumps blocker widely used in medicine. However, mechanisms of nifedipine action in blood are not clear. In particular, the influence of nifedipine on erythrocytes is far from completely understood. In this work, applying scanning flow cytometry, we observed experimentally for the first time the dynamics behind a significant increase of HCO 3 − /Cl − transmembrane exchange rate of CDB3 (main anion exchanger, AE1, Band 3, SLC4A1) of human erythrocytes in the presence of nifedipine in blood. It was found that the rate of CDB3 activation is not limited by the rate of nifedipine binding and/or Ca 2+ transport. In order to explain the experimental data, we suggested a kinetic model assuming that the rate of CDB3 activation is limited by the dynamics of the balance between two intracellular processes (1) the activation of CDB3 limited by its interaction with intracellular Ca 2+ , and (2) the spontaneous deactivation of CDB3. Thus the use of scanning flow cytometry allowed to clarify quantitatively the molecular kinetic mechanism of nifedipine action on human erythrocytes. In particular, the efficiency (~30) and rates of activation (~0.3 min −1 ) and deactivation (~10 −3 min −1 ) of CDB3 in human erythrocytes was evaluated for two donors.Nifedipine is widely used in medicine under the name of Adalat and other drugs. One common usage is the treatment of cardiovascular pathology such as atherosclerosis, coronary heart disease, hypertension, cerebral ischemia, and others (1). Other uses include painful spasms of the esophagus (2,3), Raynaud's phenomenon (4), tocolytic therapy (5). However, the effect of the treatment by nifedipine is not always positive (6). In particular, it is not clear (7) the influence of nifedipine on the rate of HCO 3− /Cl − transmembrane CDB3 protein (AE1, Band 3), which plays an important role in bicarbonate metabolism (8). Overall, a more complete understanding of nifedipine action in blood is needed.Nifedipine belongs to the subclass of dihydropyridines (DHPs), which are known as inhibitors of Ca 2+ transport across the erythrocyte membrane in both pathways: (1) inward leak through Ca 2+ entry channels (9-11), and (2) extrusion by plasma membrane Ca 2+ pumps (PMCA) (12,13). It was reported (13) that about 50% inhibition of PMCA was obtained at extracellular nifedipine concentration of 300 μM. Interestingly, the same extracellular concentration of 300 μM nifedipine was reported (14) to cause less (about 30%) inhibition of Ca 2+ entry channels of erythrocyte membrane. Stronger inhibition of PMCA than entry channels leads to the accumulation of intracellular Ca 2+ in erythrocytes in the presence of extracellular

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Bicarbonate transport in health and disease

Cited by 79 publications

References 277 publications

Emerging roles of Na+/H+ exchangers in epilepsy and developmental brain disorders

Emerging roles of Na+/H+ exchangers in epilepsy and developmental brain disorders

Bicarbonate Increases Ischemia-Reperfusion Damage by Inhibiting Mitophagy

Proposed Dynamics of CDB3 Activation in Human Erythrocytes by Nifedipine Studied with Scanning Flow Cytometry

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