Proton inhibition of GABA-activated current in rat primary sensory neurons

Zhai, Jin; Peoples, Robert W.; Li, Chaoying

doi:10.1007/s004240050550

Cited by 28 publications

(32 citation statements)

References 27 publications

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“…Variations in the level of endogenous ions in the CNS represent a rapid and effective method for regulating receptor function (Kaila, 1994;Smart et al, 1994). Previous studies have indicated that protons can differentially affect neuronal GABA A receptors, resulting in potentiation, inhibition, or no effect on GABA-activated responses (Kaila, 1994;Robello et al, 1994;Pasternack et al, 1996;Zhai et al, 1998;Krishek and Smart, 2001). This variability to pH has been ascribed to differences in the neuronal receptor subunit composition that can be reproduced to some extent using recombinant GABA A receptors .…”

Section: Abstract: Gaba a Receptor; Ph Modulation; ␤ Subunit; Histidmentioning

confidence: 99%

Identification of a β Subunit TM2 Residue Mediating Proton Modulation of GABA Type A Receptors

Wilkins¹,

Hosie²,

Smart³

2002

J. Neurosci.

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GABA type A (GABA A ) receptors are functionally regulated by external protons in a manner dependent on the receptor subunit composition. Although H ϩ can regulate the open probability of single GABA ion channels, exactly what residues and receptor subunits are responsible for proton-induced modulation remain unknown. This study resolves this issue by using recombinant ␣1␤i subunit GABA A receptors expressed in human embryonic kidney cells. The potentiating effect of low external pH on GABA responses exhibited p Ka in accord with the involvement of histidine and/or cysteine residues. The exposure of GABA A receptors to the histidine-modifying reagent DEPC ablated regulation by H ϩ , implicating the involvement of histidine residues rather than cysteines in proton regulation. Site-specific substitution of all conserved external histidines to alanine on the ␤ subunits revealed that H267 alone, in the TM2 domain, is important for H ϩ regulation. These results are interpreted as a direct protonation of H267 on ␣1␤i receptors rather than an involvement in signal transduction. The opposing functional effects induced by Zn 2ϩ and H ϩ at this single histidine residue most likely reflect differences in charge delocalization on the imidazole rings in the mouth of the GABA A receptor ion channel. Additional substitutions of H267 in ␤ subunits with other residues possessing charged side chains (glutamate and lysine) reveal that this area of the ion channel can profoundly influence the functional properties of GABA A receptors.

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Section: Abstract: Gaba a Receptor; Ph Modulation; ␤ Subunit; Histidmentioning

confidence: 99%

Identification of a β Subunit TM2 Residue Mediating Proton Modulation of GABA Type A Receptors

Wilkins¹,

Hosie²,

Smart³

2002

J. Neurosci.

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“…Protons also neutralize negative surface charge, shifting the voltage-dependence of Ca 2+ channels to more positive potentials [97,98] . Various studies have indicated that protons can affect neuronal GABA A receptors differently depending on the receptor subunit composition, resulting in potentiation, inhibition, or no effect on GABA-induced responses [12,57,[102][103][104][105][106] (Fig. 1).…”

Section: Vgccs Synaptic Vesicles Are Always Acidified Bymentioning

confidence: 99%

Proton production, regulation and pathophysiological roles in the mammalian brain

Zeng

2012

Neurosci. Bull.

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Abstract:The recent demonstration of proton signaling in C. elegans muscle contraction suggests a novel mechanism for proton-based intercellular communication and has stimulated enthusiasm for exploring proton signaling in higher organisms. Emerging evidence indicates that protons are produced and regulated in localized space and time. Furthermore, identification of proton regulators and sensors in the brain leads to the speculation that proton production and regulation may be of major importance for both physiological and pathological functions ranging from nociception to learning and memory. Extracellular protons may play a role in signal transmission by not only acting on adjacent cells but also affecting the cell from which they were released. In this review, we summarize the upstream and downstream pathways of proton production and regulation in the mammalian brain, with special emphasis on the proton extruders and sensors that are critical in the homeostatic regulation of pH, and discuss their potential roles in proton signaling under normal and pathophysiological conditions.

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“…These findings suggest that protons modulate the desensitization of GABA A receptors in a subunit-dependent manner. A reduction in extracellular pH has been reported to either have no influence on desensitization (Pasternack et al 1996;Robello et al 1994) or decrease desensitization (Mozrzymas et al 2003;Zhai et al 1998) of GABA A receptors on native neurons. These inconsistent data may be due to the presence of multiple population of GABA A receptor isoforms on these neurons.…”

Section: Incorporation Of a ␥2l Or A ␦ Subunit Into ␣1␤3 Receptors Almentioning

confidence: 99%

“…However, it was reported that exposure of the HEK cells to Krebs solution at pH 5.4 for minutes induced negligible alterations of intracellular pH (Krishek et al 1996). In addition, limited acidification of the intracellular environment may not affect GABA A receptor function (Pasternack et al 1992;Zhai et al 1998). Therefore we interpreted the 28-s application data in the same FIG. 4.…”

Section: Reduction Of Ph Enhanced Steady-state Currents Of ␣1␤3␦ Recementioning

confidence: 99%

“…There is substantial evidence suggesting that extracellular pH modulated the function of native and recombinant GABA A receptors (Krishek and Smart 2001; Krishek et al. 1996;Mozrzymas et al 2003;Pasternack et al 1996;Robello et al 1994Robello et al , 2000 Wilkins et al 2002;Zhai et al 1998). Low pHs enhanced ␣1␤1, ␣1␤2, and ␣1␤1␦ GABA A receptor currents (Krishek et al 1996; Wilkins et al 2002).…”

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confidence: 99%

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Proton Modulation of α1β3δ GABA_A Receptor Channel Gating and Desensitization

Feng

Macdonald²

2004

Journal of Neurophysiology

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Feng, Hua-Jun and Robert L. Macdonald. Proton modulation of ␣1␤3␦ GABA A receptor channel gating and desensitization. J Neurophysiol 92: 1577-1585, 2004. First published May 19, 2004 10.1152/jn.00285.2004. ␣␤␥ GABA A receptor currents are phasic and desensitizing, whereas ␣␤␦ GABA A receptor currents are tonic and have no fast desensitization. ␣␤␥ receptors are subsynaptic and mediate phasic inhibition, whereas ␣␤␦ receptors are extra-or perisynaptic and mediate tonic inhibition. Given the different roles of these GABA A receptor isoforms and the fact that GABA A receptors are allosterically regulated by extracellular pH in a subunit-dependent manner, we compared the effects of changing pH on rat ␦ or ␥2L subunit-containing GABA A receptor currents. Human embryonic kidney cells (HEK293T) were transfected with cDNAs encoding rat ␣1, ␤3, ␥2L, or ␦ GABA A receptor subunits in several binary and ternary combinations, and whole cell and single channel patch-clamp recordings were obtained. Lowering pH substantially enhanced ␣1␤3 receptor currents. This effect was significantly more pronounced for ternary ␣1␤3␦ receptors, whereas ternary ␣1␤3␥2L receptors were relatively insensitive to lowered pH. Lowering pH did not affect the extent of desensitization of ␣1␤3 and ␣1␤3␥2L receptor currents, but significantly increased the extent of desensitization of ␣1␤3␦ receptor currents. Lowering pH prolonged deactivation of ␣1␤3 and ␣1␤3␦ receptor currents and enhanced the "steady-state" currents of ␣1␤3␦ receptors evoked by long-duration (28 s) GABA applications. Lowering pH significantly increased mean open duration of ␣1␤3␦ steadystate single channel currents due to introduction of a longer-duration open state, suggesting that low pH enhances ␣1␤3␦ receptor steadystate currents by modifying GABA A receptor gating properties. Mehta and Ticku 1999;Olsen and Macdonald 2002). Native GABA A receptors may be composed primarily of ␣␤␥ and ␣␤␦ isoforms (McKernan and Whiting 1996). The ␣␤␥ isoforms, found mainly in GABAergic synapses, are thought to mediate phasic inhibition, whereas the ␣␤␦ isoforms selectively target extra-or perisynaptic membranes, where they have been proposed to exert tonic inhibition (Bai et al. 2001; Isaacson 2000;Lerma et al. 1986; Nusser et al. 1998;Saxena and Macdonald 1994;Stell et al. 2003;Wei et al. 2003).GABA A receptors are allosterically modulated by a variety of compounds in a subunit-dependent manner (Pritchett et al. 1989; Sundstrom-Poromaa et al. 2002;Thompson et al. 1999;Wafford et al. 1994;Wallner et al. 2003). It has been recently reported that ␣␤␥ and ␣␤␦ GABA A receptors are differentially modulated by neurosteroids and barbiturates (Feng et al. 2002;Wohlfarth et al. 2002), suggesting that phasic inhibition and tonic inhibition may make different contributions to the inhibitory responses in physiological or pathophysiological conditions.Alteration of extracellular proton concentration (pH) has been shown to occur in pathophysiological conditions such as seizures and to influence neuronal exc...

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Proton inhibition of GABA-activated current in rat primary sensory neurons

Cited by 28 publications

References 27 publications

Identification of a β Subunit TM2 Residue Mediating Proton Modulation of GABA Type A Receptors

Identification of a β Subunit TM2 Residue Mediating Proton Modulation of GABA Type A Receptors

Proton production, regulation and pathophysiological roles in the mammalian brain

Proton Modulation of α1β3δ GABA_A Receptor Channel Gating and Desensitization

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Proton inhibition of GABA-activated current in rat primary sensory neurons

Cited by 28 publications

References 27 publications

Identification of a β Subunit TM2 Residue Mediating Proton Modulation of GABA Type A Receptors

Identification of a β Subunit TM2 Residue Mediating Proton Modulation of GABA Type A Receptors

Proton production, regulation and pathophysiological roles in the mammalian brain

Proton Modulation of α1β3δ GABAA Receptor Channel Gating and Desensitization

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Proton Modulation of α1β3δ GABA_A Receptor Channel Gating and Desensitization