Acidosis of hippocampal neurones mediated by a plasmalemmal Ca2+/H+ pump

Trapp, Stefan; Lückermann, Mark; Kaila, Kai; Ballanyi, Klaus

doi:10.1097/00001756-199608120-00029

Cited by 78 publications

(69 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, other ions including Na ϩ and H ϩ have also been proposed to play a critical role. As Slc4a8 mediates Na ϩ -coupled anion exchange, its activity increases the [Na ϩ ] i concentration, which in turn may increase the [Ca 2ϩ ] i via the Na ϩ /Ca 2ϩ exchanger (Mulkey and Zucker, 1992;Reuter and Porzig, 1995), whereas Ca 2ϩ extrusion via the ATP-driven Ca 2ϩ /H ϩ exchanger is probably not severely impaired by the reduction in baseline pH i (Schwiening et al, 1993;Trapp et al, 1996). Following this scenario, disruption of Slc4a8 may result in a lower [Ca 2ϩ ] i and hence a reduction of spontaneous synaptic vesicle release.…”

Section: How Can Disruption Of Slc4a8 Affect Neurotransmitter Release?mentioning

confidence: 99%

Synaptic Glutamate Release Is Modulated by the Na⁺-Driven Cl⁻/HCO₃⁻Exchanger Slc4a8

Sinning

Liebmann²,

Kougioumtzes³

et al. 2011

J. Neurosci.

View full text Add to dashboard Cite

On the one hand, neuronal activity can cause changes in pH; on the other hand, changes in pH can modulate neuronal activity. Consequently, the pH of the brain is regulated at various levels. Here we show that steady-state pH and acid extrusion were diminished in cultured hippocampal neurons of mice with a targeted disruption of the Na ϩ -driven Cl Ϫ /HCO 3 Ϫ exchanger Slc4a8. Because Slc4a8 was found to predominantly localize to presynaptic nerve endings, we hypothesize that Slc4a8 is a key regulator of presynaptic pH. Supporting this hypothesis, spontaneous glutamate release in the CA1 pyramidal layer was reduced but could be rescued by increasing the intracellular pH. The reduced excitability in vitro correlated with an increased seizure threshold in vivo. Together with the altered kinetics of stimulated synaptic vesicle release, these data suggest that Slc4a8 modulates glutamate release in a pH-dependent manner.

show abstract

Section: How Can Disruption Of Slc4a8 Affect Neurotransmitter Release?mentioning

confidence: 99%

Synaptic Glutamate Release Is Modulated by the Na⁺-Driven Cl⁻/HCO₃⁻Exchanger Slc4a8

Sinning

Liebmann²,

Kougioumtzes³

et al. 2011

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…The proposed mechanisms by which increases in [Ca 2ϩ ] i transmit intracellular acidification include: (i) the mitochondrial Ca 2ϩ -scavenging pathway leading to a collapse of the negative potential across the inner mitochondrial membrane and a subsequent leak of protons (31), (ii) the displacement of protons from Ca 2ϩ -buffering proteins (32,33), or (iii) a Ca 2ϩ -H ϩ antiport by plasmalemmal Ca 2ϩ -ATPases (29,34). A mitochondrial Ca 2ϩ uptake has already been shown to underly a Ca 2ϩ influx-dependent acidification of DRG neurons in response to membrane depolarization (35).…”

Section: Capsaicin-induced Changes Of the Ph I In Rat Dorsal Rootmentioning

confidence: 99%

TRPV1 Acts as Proton Channel to Induce Acidification in Nociceptive Neurons

Hellwig

Plant

Janson

et al. 2004

Journal of Biological Chemistry

139

101

View full text Add to dashboard Cite

The low extracellular pH of inflamed or ischemic tissues enhances painful sensations by sensitizing and activating the vanilloid receptor 1 (TRPV1). We report here that activation of TRPV1 results in a marked intracellular acidification in nociceptive dorsal root ganglion neurons and in a heterologous expression system. A characterization of the underlying mechanisms revealed a Ca 2؉ -dependent intracellular acidification operating at neutral pH and an additional as yet unrecognized direct proton conductance through the poorly selective TRPV1 pore operating in acidic extracellular media. Large organic cations permeate through the activated TRPV1 pore even in the presence of physiological concentrations of Na ؉ , Mg 2؉ , and Ca 2؉ . The wide pore and the unexpectedly high proton permeability of TRPV1 point to a proton hopping permeation mechanism along the water-filled channel pore. In acidic media, the high relative proton permeability through TRPV1 defines a novel proton entry mechanism in nociceptive neurons.During ischemia or inflammation, pain sensation is augmented by the acidic extracellular pH (pH ext ). 1 A␦-and C-fiber neurons sense extracellular acid by means of two different classes of cation channels, namely TRPV1, the founding member of the vanilloid receptor-like transient receptor potential channel family (1, 2), and the acid-sensing ion channels (ASIC) (3, 4). Both channel types are expressed in small diameter dorsal root ganglion (DRG) neurons, and their role in mediating inflammatory hyperalgesia has been proven by gene deletion techniques (5-7). TRPV1, a poorly selective cation channel, integrates multiple pain-inducing stimuli, including noxious heat, vanilloids, and acidic extracellular pH (1, 8 -10). Inflammatory mediators such as bradykinin, serotonin, histamine, or prostaglandins further stimulate TRPV1 activity either by protein kinase C-dependent signals (11-13), by a release from a phosphatidylinositol 4,5-bisphosphate-dependent inhibition (14,15), by formation of 12-lipoxygenase products (16), or by a protein kinase A-mediated recovery from inactivation (17). Furthermore, extracellular acidification shifts the activation of TRPV1 toward lower temperature or ligand thresholds by protonation of an amino acid located in the vicinity of the pore loop (18). Although the role of the external pH ext in modulating TRPV1 activity is well established, a possible impact of TRPV1 activation on the intracellular pH has not been studied.A Ca 2ϩ influx component through activated voltage-or ligand-gated cation channels has been recognized to lower the intracellular pH (pH i ) in neurons or in neuroendocrine cells (19,20). We therefore asked the question whether activation of the Ca 2ϩ -permeable TRPV1 may also mediate intracellular acidification in native rat dorsal root ganglion neurons or in a heterologous expression system. Our results provide evidence for two independent TRPV1-mediated acidification signals, including an as yet unrecognized direct proton conductance through the activated TRPV1 p...

show abstract

“…While pH affects neural activity, neural activity causes pH alterations that vary in location and time (Chen and Chesler, 1992;Dulla et al, 2005;Makani and Chesler, 2007). Local pH changes occur in the brain during normal function (Chesler and Kaila, 1992;Magnotta et al, 2012), and neuronal firing causes both intracellular and extracellular pH shifts (Chesler, 2003;Chesler and Kaila, 1992;Kim and Trussell, 2009;Trapp et al, 1996). Rapid changes in intracellular pH have been observed at Drosophila nerve terminals during high-frequency in vivo activity (Caldwell et al, 2013;Rossano et al, 2013), while in the mammalian CNS, intense and synchronous activity of neural networks is accompanied by an initial alkalinization followed by a slower wave of acidification of the extracellular environment (DeVries, 2001;Du et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Neuronal hyperactivity causes Na+/H+ exchanger-induced extracellular acidification at active synapses

Chiacchiaretta

Latifi

Bramini

et al. 2017

Journal of Cell Science

View full text Add to dashboard Cite

Extracellular pH impacts on neuronal activity, which is in turn an important determinant of extracellular H + concentration. The aim of this study was to describe the spatio-temporal dynamics of extracellular pH at synaptic sites during neuronal hyperexcitability. To address this issue we created ex.E 2 GFP, a membrane-targeted extracellular ratiometric pH indicator that is exquisitely sensitive to acidic shifts. By monitoring ex.E 2 GFP fluorescence in real time in primary cortical neurons, we were able to quantify pH fluctuations during network hyperexcitability induced by convulsant drugs or highfrequency electrical stimulation. Sustained hyperactivity caused a pH decrease that was reversible upon silencing of neuronal activity and located at active synapses. This acidic shift was not attributable to the outflow of synaptic vesicle H + into the cleft nor to the activity of membrane-exposed H + V-ATPase, but rather to the activity of the Na + /H + -exchanger. Our data demonstrate that extracellular synaptic pH shifts take place during epileptic-like activity of neural cultures, emphasizing the strict links existing between synaptic activity and synaptic pH. This evidence may contribute to the understanding of the physio-pathological mechanisms associated with hyperexcitability in the epileptic brain.

show abstract

Acidosis of hippocampal neurones mediated by a plasmalemmal Ca2+/H+ pump

Cited by 78 publications

References 0 publications

Synaptic Glutamate Release Is Modulated by the Na⁺-Driven Cl⁻/HCO₃⁻Exchanger Slc4a8

Synaptic Glutamate Release Is Modulated by the Na⁺-Driven Cl⁻/HCO₃⁻Exchanger Slc4a8

TRPV1 Acts as Proton Channel to Induce Acidification in Nociceptive Neurons

Neuronal hyperactivity causes Na+/H+ exchanger-induced extracellular acidification at active synapses

Contact Info

Product

Resources

About

Acidosis of hippocampal neurones mediated by a plasmalemmal Ca2+/H+ pump

Cited by 78 publications

References 0 publications

Synaptic Glutamate Release Is Modulated by the Na+-Driven Cl−/HCO3−Exchanger Slc4a8

Synaptic Glutamate Release Is Modulated by the Na+-Driven Cl−/HCO3−Exchanger Slc4a8

TRPV1 Acts as Proton Channel to Induce Acidification in Nociceptive Neurons

Neuronal hyperactivity causes Na+/H+ exchanger-induced extracellular acidification at active synapses

Contact Info

Product

Resources

About

Synaptic Glutamate Release Is Modulated by the Na⁺-Driven Cl⁻/HCO₃⁻Exchanger Slc4a8

Synaptic Glutamate Release Is Modulated by the Na⁺-Driven Cl⁻/HCO₃⁻Exchanger Slc4a8