Modulation of pH by neuronal activity

Chesler, Mitchell; Kaila, Kai

doi:10.1016/0166-2236(92)90191-a

Cited by 493 publications

(370 citation statements)

References 56 publications

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“…Changes in pH o have profound influence on the physiology of neurons [3], and in pathological conditions affect the outcome of neuronal injury [4]. Mild acidosis, for example, has been reported to reduce excitatory injury of neurons [5] likely due to proton inhibition of NMDA channels.…”

Section: Introductionmentioning

confidence: 99%

Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases

Xiong

Pignataro²,

et al. 2008

Current Opinion in Pharmacology

211

161

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A significant drop of tissue pH or acidosis is a common feature of acute neurological conditions such as ischemic stroke, brain trauma, and epileptic seizures. Acid-sensing ion channels, or ASICs, are proton-gated cation channels widely expressed in peripheral sensory neurons and in the neurons of the central nervous system. Recent studies have demonstrated that activation of these channels by protons plays an important role in a variety of physiological and pathological processes such as nociception, mechanosensation, synaptic plasticity, and acidosis-mediated neuronal injury. This review provides an overview of the recent advance in electrophysiological, pharmacological characterization of ASICs, and their role in neurological diseases. Therapeutic potential of current available ASIC inhibitors is discussed.

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Section: Introductionmentioning

confidence: 99%

Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases

Xiong

Pignataro²,

et al. 2008

Current Opinion in Pharmacology

211

161

View full text Add to dashboard Cite

show abstract

“…Interstitial pH undergoes multiphasic changes during normal synaptic transmission and much larger changes during seizure activity and ischemia, during which pH levels can fall by 0.2-0.6 pH units (Siesjo, 1985;Balestrino and Somjen, 1988;Nedergaard et al, 1991;Chesler and Kaila, 1992). Because neuronal injury during both seizure and ischemia is associated with glutamate release (Hirano et al, 2003) and NMDA receptor activation, mild acidification of the extracellular space in the penumbra might be expected to limit the extent of glutamate-induced neurotoxicity, although acidification in the infarct core can be harmful.…”

Section: Introductionmentioning

confidence: 99%

Protons Trap NR1/NR2B NMDA Receptors in a Nonconducting State

Banke¹,

Dravid²,

Traynelis³

2005

J. Neurosci.

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NMDA receptors are highly expressed in the CNS and are involved in excitatory synaptic transmission, as well as synaptic plasticity. Given that overstimulation of NMDA receptors can cause cell death, it is not surprising that these channels are under tight control by a series of inhibitory extracellular ions, including zinc, magnesium, and H ϩ . We studied the inhibition by extracellular protons of recombinant NMDA receptor NR1/NR2B single-channel and macroscopic responses in transiently transfected human embryonic kidney HEK 293 cells using patch-clamp techniques. We report that proton inhibition proceeds identically in the absence or presence of agonist, which rules out the possibility that protonation inhibits receptors by altering coagonist binding. The response of macroscopic currents in excised patches to rapid jumps in pH was used to estimate the microscopic association and dissociation rates for protons, which were 1.4 ϫ 10 9 M Ϫ1 sec Ϫ1 and 110 -196 sec Ϫ1 , respectively (K d corresponds to pH 7.2). Protons reduce the open probability without altering the time course of desensitization or deactivation. Protons appear to slow at least one time constant describing the intra-activation shut-time histogram and modestly reduce channel open time, which we interpret to reflect a reduction in the overall channel activation rate and possible proton-induced termination of openings. This is consistent with a modest proton-dependent slowing of the macroscopic response rise time. From these data, we propose a physical model of proton inhibition that can describe macroscopic and single-channel properties of NMDA receptor function over a range of pH values.

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“…Extracellular CA has been shown to govern the generation and regulation of activity-dependent pH transients in brain (Chesler and Kaila, 1992). However, the localization of this enzyme activity has been uncertain.…”

mentioning

confidence: 99%

Surface carbonic anhydrase activity on astrocytes and neurons facilitates lactate transport

Svichar

Chesler

2003

Glia

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A number of studies have provided physiological evidence for extracellular carbonic anhydrase (CA) in brain. Association of extracellular CA with glia has been limited to functional studies of gliotic slices and retinal Muller cells. While astrocytes contain intracellular CA, there has been no direct evidence for surface CA on these cells. In fact, some morphological studies suggest that the extracellular CA in brain parenchyma resides on neurons, not glia. There has been no functional demonstration of extracellular CA activity on CNS neurons, however. Here we capitalized on the H ϩ dependence of inward lactate transport to reveal functional extracellular CA activity on cultured astrocytes and acutely isolated hippocampal pyramidal neurons. Exposure to 20 mM L-lactate produced a rapid acidification of astrocytes that was reversibly blocked by 10 M benzolamide. The lactate-induced acidification (LIA) was also blocked by a dextran-conjugated CA inhibitor. In CO 2 /HCO 3 Ϫ -free, HEPES-buffered media, the LIA was largely unaffected. Acutely dissociated hippocampal pyramidal neurons underwent a similar LIA that was reversibly blocked by benzolamide. Surface CA is likely to facilitate lactate transport by enabling rapid replenishment (i.e., buffering) of surface H ϩ required for inward lactate-H ϩ cotransport. These results demonstrate functional surface CA for the first time on individual mammalian astrocytes and neurons and suggest that this enzyme may play a role in the utilization of monocarboxylate substrates such as lactate and pyruvate by the brain. GLIA 41:415-419, 2003.

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Modulation of pH by neuronal activity

Cited by 493 publications

References 56 publications

Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases

Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases

Protons Trap NR1/NR2B NMDA Receptors in a Nonconducting State

Surface carbonic anhydrase activity on astrocytes and neurons facilitates lactate transport

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