The Na<sup>+</sup>/H<sup>+</sup> exchanger is a major pH regulator in GABAergic presynaptic nerve terminals synapsing onto rat CA3 pyramidal neurons

Jang, Il‐Sung; Brodwick, Malcolm S.; Wang, Zhiming; Jeong, Hyo‐Jin; Choi, Byung Jin; Akaike, Norio

doi:10.1111/j.1471-4159.2006.04168.x

Cited by 33 publications

(28 citation statements)

References 49 publications

(122 reference statements)

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“…Third, our studies indicate that NHE1 is an important neurotransmitter regulator, in agreement with previous work in hippocampal cultures (Trudeau et al 1999;Jang et al 2006). Our studies show that GABAergic synapses onto MHb neurones may require the activation of NHE1.…”

Section: Discussionsupporting

confidence: 79%

“…This is supported by the observation that bath application of zoniporide completely blocked neurotransmission. In the CNS, glutamatergic nerve terminals express functional Na + -H + exchangers (Trudeau et al 1999;Rocha et al 2008), and studies in dissociated hippocampal neurones and cerebellar granule cells indicate that GABAergic presynaptic terminals also have such a pH regulatory system (Jang et al 2006;Dietrich & Morad, 2010). Our results show that inhibition of NHE1 with zoniporide blocks synaptic neurotransmission to the same extent as TTX, bicuculline and CdCl 2 , indicating that this ion exchanger is critical for neurotransmitter release.…”

Section: Discussionsupporting

confidence: 53%

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Cross‐reactivity of acid‐sensing ion channel and Na⁺–H⁺ exchanger antagonists with nicotinic acetylcholine receptors

Santos-Torres

Ślimak

Auer

et al. 2011

The Journal of Physiology

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Non-technical summary Cardiovascular disease and high blood pressure (hypertension) are frequent in the human population. Amiloride is commonly given as a diuretic to reduce hypertension without eliminating potassium, while zoniporide is used to aid in recovery after cardiac failure. We show here that high concentrations of these drugs have additional effects on nicotinic receptors that are present in the brain and body. The possibility that these drugs could affect nicotinic receptors when given as medications should be further investigated.Abstract Nicotinic acetylcholine receptors (nAChRs) are widely distributed throughout the mammalian central and peripheral nervous systems, where they contribute to neuronal excitability and synaptic communication. It has been reported that nAChRs are modulated by BK channels and that BK channels, in turn, are inhibited by acid-sensing ion channels (ASICs). Here we investigate the possible functional interaction between these channels in medial habenula (MHb) neurones. We report that selective antagonists of large-conductance calcium-activated potassium channels and ASIC1a channels, paxilline and psalmotoxin 1, respectively, did not induce detectable changes in nicotine-evoked currents. In contrast, the non-selective ASIC and Na + -H + exchanger (NHE1) antagonists, amiloride and its analogues, suppressed nicotine-evoked responses in MHb neurones of wild-type and ASIC2 null mice, excluding a possible involvement of ASIC2 in the nAChR inhibition by amiloride. Zoniporide, a more selective inhibitor of NHE1, reversibly inhibited α3β4-, α7-and α4-containing ( * ) nAChRs in Xenopus oocytes and in brain slices, as well as in PS120 cells deficient in NHE1 and virally transduced with nAChRs, suggesting a generalized effect of zoniporide in most neuronal nAChR subtypes. Independently from nAChR antagonism, zoniporide profoundly blocked synaptic transmission onto MHb neurones without affecting glutamatergic and GABA receptors. Taken together, these results indicate that amiloride and zoniporide, which are clinically used to treat hypertension and cardiovascular disease, have an inhibitory effect on neuronal nAChRs when used experimentally at high doses. The possible cross-reactivity of these compounds with nAChRs in vivo will require further investigation.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionsupporting

confidence: 53%

Cross‐reactivity of acid‐sensing ion channel and Na⁺–H⁺ exchanger antagonists with nicotinic acetylcholine receptors

Santos-Torres

Ślimak

Auer

et al. 2011

The Journal of Physiology

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“…However, in view of our localization data (Jacobs et al, 2008) and unpublished data from our laboratory, Slc4a10 appears to be the more likely candidate. Similar to Slc4a10, the Na ϩ -HCO 3 Ϫ cotransporter Slc4a7, which also mediates acid extrusion, has been found to be localized to the postsynaptic side (Park et al, 2010), whereas it has been suggested that the Na ϩ /H ϩ exchanger Slc9a1 is present in presynaptic nerve endings (Jang et al, 2006;Dietrich and Morad, 2010).…”

Section: Discussionmentioning

confidence: 99%

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

Sinning

Liebmann²,

Kougioumtzes³

et al. 2011

J. Neurosci.

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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.

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“…However, in order to provide an insight into whether another alternative route for Na + entry may have contributed in our preparation, we added amiloride to the bumetanide already in the mouse nerve bath (Fig. 8c, d), where amiloride is a blocker of Na + -H + ion exchange (NHE1) in white matter (e.g., [25,32,34,38]). The influx of Na + by this mechanism is predicted to be temperature dependent [12].…”

Section: Membrane Potential Recordingmentioning

confidence: 99%

Acute temperature sensitivity in optic nerve axons explained by an electrogenic membrane potential

Coates

Woolnough

Masters

et al. 2015

Pflugers Arch - Eur J Physiol

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Classical work in squid axon reports resting membrane potential is independent of temperature, but our findings suggest that this is not the case for axons in mammalian optic nerve. Refractory period duration changes over 10 times between 37 °C and room temperature, and afterpotential polarity is also acutely temperature sensitive, inconsistent with changes in temperature impacting nerve function only through altered rates of ion channel gating kinetics. Our evidence suggests that the membrane potential is enhanced by warming, an effect reduced by exposure to ouabain. The temperature dependence can be explained if axonal Na(+)/K(+) ATPase continuously expels Na(+) ions that enter axons largely electroneutrally, thereby adding a substantial electrogenic component to the membrane potential. Block of the Na(+) transporter NKCC1 with bumetanide increases refractoriness, like depolarization, indicating that this is a probable route by which Na(+) enters, raising the expectation that the rate of electroneutral Na(+) influx increases with temperature and suggesting a temperature-dependent transmembrane Na(+) cycle that contributes to membrane potential.

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The Na⁺/H⁺ exchanger is a major pH regulator in GABAergic presynaptic nerve terminals synapsing onto rat CA3 pyramidal neurons

Cited by 33 publications

References 49 publications

Cross‐reactivity of acid‐sensing ion channel and Na⁺–H⁺ exchanger antagonists with nicotinic acetylcholine receptors

Cross‐reactivity of acid‐sensing ion channel and Na⁺–H⁺ exchanger antagonists with nicotinic acetylcholine receptors

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

Acute temperature sensitivity in optic nerve axons explained by an electrogenic membrane potential

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The Na+/H+ exchanger is a major pH regulator in GABAergic presynaptic nerve terminals synapsing onto rat CA3 pyramidal neurons

Cited by 33 publications

References 49 publications

Cross‐reactivity of acid‐sensing ion channel and Na+–H+ exchanger antagonists with nicotinic acetylcholine receptors

Cross‐reactivity of acid‐sensing ion channel and Na+–H+ exchanger antagonists with nicotinic acetylcholine receptors

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

Acute temperature sensitivity in optic nerve axons explained by an electrogenic membrane potential

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The Na⁺/H⁺ exchanger is a major pH regulator in GABAergic presynaptic nerve terminals synapsing onto rat CA3 pyramidal neurons

Cross‐reactivity of acid‐sensing ion channel and Na⁺–H⁺ exchanger antagonists with nicotinic acetylcholine receptors

Cross‐reactivity of acid‐sensing ion channel and Na⁺–H⁺ exchanger antagonists with nicotinic acetylcholine receptors

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