Regulation of pH in the mammalian central nervous system under normal and pathological conditions: Facts and hypotheses

Obara, Marta; Szeliga, Monika; Albrecht, Jan

doi:10.1016/j.neuint.2007.10.015

Cited by 148 publications

(192 citation statements)

References 219 publications

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“…The same effects on V j gating were found in all seven experiments using intracellular acidification and all six experiments using alkalinization, including the one shown in Fig. S3, where both CO 2 and NH 4 Cl were applied in the same experiment. 4 Cl.…”

supporting

confidence: 71%

“…4B) as pH i starts to decrease has been described (21). Application of 15 mM NH 4 Cl increased pH i from 7.2 ± 0.1 to 8.1 ± 0.2 (n = 18) and increased g j on average to 1.8 times its value at pH i = 7.2. Fitting the Hill equation to the g j -pH i relation for Cx45 (circles in Fig.…”

mentioning

confidence: 92%

“…cell-cell coupling | pH-dependent gating | EGFP | hemichannel | connexon C hanges in intracellular pH (pH i ) take place under different physiological and pathological conditions, and H + ions have a broad effect on cell function including cell-cell electrical and metabolic communication mediated by gap junctions (GJs) and paracrine signaling through nonjunctional/unapposed hemichannels (1)(2)(3)(4). Modest pH i changes have been observed under normal physiological conditions [e.g., changes of neuronal activity or the resting potential (5, 6)], and greater changes occur under pathological conditions such as hypoxia, ischemia, or epilepsy (4,7,8).…”

mentioning

confidence: 99%

“…Modest pH i changes have been observed under normal physiological conditions [e.g., changes of neuronal activity or the resting potential (5, 6)], and greater changes occur under pathological conditions such as hypoxia, ischemia, or epilepsy (4,7,8).…”

mentioning

confidence: 99%

“…Cells were exposed to modified Krebs-Ringer (MKR) solutions bubbled with CO 2 or with added NH 4 Cl, and the unesterified form of the ratiometric fluorescent probe, 2,7-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF), was dialyzed into the cells from the recording pipettes to measure pH i (Fig. 1A) (19).…”

mentioning

confidence: 99%

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pH-dependent modulation of voltage gating in connexin45 homotypic and connexin45/connexin43 heterotypic gap junctions

Palacios-Prado

Briggs

Skeberdis

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Intracellular pH (pH i ) can change during physiological and pathological conditions causing significant changes of electrical and metabolic cell-cell communication through gap junction (GJ) channels. In HeLa cells expressing wild-type connexin45 (Cx45) as well as Cx45 and Cx43 tagged with EGFP, we examined how pH i affects junctional conductance (g j ) and g j dependence on transjunctional voltage (V j ). To characterize V j gating, we fit the g j -V j relation using a stochastic four-state model containing one V j -sensitive gate in each apposed hemichannel (aHC); aHC open probability was a Boltzmann function of the fraction of V j across it. Using the model, we estimated gating parameters characterizing sensitivity to V j and number of functional channels. In homotypic Cx45 and heterotypic Cx45/Cx43-EGFP GJs, pH i changes from 7.2 to ∼8.0 shifted g j -V j dependence of Cx45 aHCs along the V j axis resulting in increased probability of GJ channels being in the fully open state without change in the slope of g j dependence on V j . In contrast, acidification shifted g j -V j dependence in the opposite direction, reducing open probability; acidification also reduced the number of functional channels. Correlation between the number of channels in Cx45-EGFP GJs and maximal g j achieved under alkaline conditions showed that only ∼4% of channels were functional. The acid dissociation constant (pK a ) of g j -pH i dependence of Cx45/Cx45 GJs was ∼7. The pK a of heterotypic Cx45/Cx43-EGFP GJs was lower, ∼6.7, between the pK a s of Cx45 and Cx43-EGFP (∼6.5) homotypic GJs. In summary, pH i significantly modulates junctional conductance of Cx45 by affecting both V j gating and number of functional channels.cell-cell coupling | pH-dependent gating | EGFP | hemichannel | connexon C hanges in intracellular pH (pH i ) take place under different physiological and pathological conditions, and H + ions have a broad effect on cell function including cell-cell electrical and metabolic communication mediated by gap junctions (GJs) and paracrine signaling through nonjunctional/unapposed hemichannels (1-4). Modest pH i changes have been observed under normal physiological conditions [e.g., changes of neuronal activity or the resting potential (5, 6)], and greater changes occur under pathological conditions such as hypoxia, ischemia, or epilepsy (4,7,8).During the last decade, significant progress has been made toward understanding the molecular mechanisms of pH-dependent modulation of GJs and hemichannels (2, 9-12). Several domains in the cytoplasmic loop and C terminus of connexin43 (Cx43) appear to be involved in pH-dependent gating (2, 9, 11, 12). Furthermore, pH-dependent interaction of connexins with other cytoplasmic proteins may be important in the remodeling of connexins and in protection from lesion spread after local ischemic injury (13,14).GJs provide channels with an inner diameter of ∼1.4 nm between the interiors of the coupled cells. This link allows the spread of electrical potential and small metabolites. Each GJ cha...

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supporting

confidence: 71%

mentioning

confidence: 92%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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pH-dependent modulation of voltage gating in connexin45 homotypic and connexin45/connexin43 heterotypic gap junctions

Palacios-Prado

Briggs

Skeberdis

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Two‐Color Emitting Colloidal Nanocrystals as Single‐Particle Ratiometric Probes of Intracellular pH

Bruni

Pedrini

Bossio

et al. 2017

Adv Funct Materials

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Intracellular pH is a key parameter in many biological mechanisms and cell metabolism and is used to detect and monitor cancer formation and brain or heart diseases. pH‐sensing is typically performed by fluorescence microscopy using pH‐responsive dyes. Accuracy is limited by the need for quantifying the absolute emission intensity in living biological samples. An alternative with a higher sensitivity and precision uses probes with a ratiometric response arising from the different pH‐sensitivity of two emission channels of a single emitter. Current ratiometric probes are complex constructs suffering from instability and cross‐readout due to their broad emission spectra. Here, we overcome such limitations using a single‐particle ratiometric pH probe based on dot‐in‐bulk CdSe/CdS nanocrystals (NCs). These nanostructures feature two fully‐separated narrow emissions with different pH sensitivity arising from radiative recombination of core‐ and shell‐localized excitons. The core emission is nearly independent of the pH, whereas the shell luminescence increases in the 3–11 pH range, resulting in a cross‐readout‐free ratiometric response as strong as 600%. In vitro microscopy demonstrates that the ratiometric response in biologic media resembles the precalibralation curve obtained through far‐field titration experiments. The NCs show good biocompatibility, enabling us to monitor in real‐time the pH in living cells.

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FXTAS Neuropathology Includes Widespread Reactive Astrogliosis and White Matter Specific Astrocyte Degeneration

Dufour,

Bartley,

McBride

et al. 2024

Annals of Neurology

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ObjectiveFragile X‐ associated Tremor/Ataxia Syndrome (FXTAS) is a late‐onset progressive genetic neurodegenerative disorder that occurs in FMR1 premutation carriers. The temporal, spatial, and cell‐type specific patterns of neurodegeneration in the FXTAS brain remain incompletely characterized. Intranuclear inclusion bodies are the neuropathological hallmark of FXTAS, which are largest and occur most frequently in astrocytes, glial cells that maintain brain homeostasis. Here, we characterized neuropathological alterations in astrocytes in multiple regions of the FXTAS brain.MethodsStriatal and cerebellar sections from FXTAS cases (n=12) and controls (n=12) were stained for the astrocyte markers Glial Fibrillary Acidic Protein (GFAP) and aldehyde dehydrogenase 1L1 (ALDH1L1) using immunohistochemistry. Reactive astrogliosis severity, the prevalence of GFAP+ fragments, and astrocyte density were scored. Double label immunofluorescence was utilized to detect co‐localization of GFAP and Cleaved Caspase 3.ResultsFXTAS cases showed widespread reactive gliosis in both grey and white matter. GFAP staining also revealed remarkably severe astrocyte pathology in FXTAS white matter ‐ characterized by a significant and visible reduction in astrocyte density (‐38.7% in striatum and ‐32.2% in cerebellum) and the widespread presence of GFAP+ fragments reminiscent of apoptotic bodies. White matter specific reductions in astrocyte density were confirmed with ALDH1L1 staining. GFAP+ astrocytes and fragments in white matter were positive for cleaved caspase‐3, suggesting that apoptosis‐mediated degeneration is responsible for reduced astrocyte counts.InterpretationWe have established that FXTAS neuropathology includes robust degeneration of astrocytes, which is specific to white matter. Since astrocytes are essential for maintaining homeostasis within the CNS, a loss of astrocytes likely further exacerbates neuropathological progression of other cell types in the FXTAS brain.This article is protected by copyright. All rights reserved.

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Regulation of pH in the mammalian central nervous system under normal and pathological conditions: Facts and hypotheses

Cited by 148 publications

References 219 publications

pH-dependent modulation of voltage gating in connexin45 homotypic and connexin45/connexin43 heterotypic gap junctions

pH-dependent modulation of voltage gating in connexin45 homotypic and connexin45/connexin43 heterotypic gap junctions

Two‐Color Emitting Colloidal Nanocrystals as Single‐Particle Ratiometric Probes of Intracellular pH

FXTAS Neuropathology Includes Widespread Reactive Astrogliosis and White Matter Specific Astrocyte Degeneration

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