1Department of Biochemistry, School of Medical Sciences, University of Bristol, University Walk, Bristol, BS8 1TD, United Kingdom.
This study investigated whether the NADPH oxidase subunit gp91phox could serve as a proton (H+) conductance pathway. Using a stable cell line expressing gp91phox, the researchers recorded outward currents associated with H+ efflux. They found that gp91phox is capable of functioning as an H+ channel, with the N-terminal region being sufficient for this activity. Histidine 115 was identified as a key residue for H+ conduction. Voltage-gated H+ currents were observed, suggesting that gp91phox can act as a voltage-sensitive pathway. The similarity between voltage-elicited and arachidonate-activated H+ flux implies a single pathway. Among homologues of gp91phox, only NOH-1S has been shown to have similar H+ conductance properties. These findings suggest that gp91phox plays a direct role in H+ transport during superoxide production.
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Area of Science:
Background:
The NADPH oxidase system is known to generate reactive oxygen species, particularly superoxide, in a process that alters membrane potential. Prior research has shown that this process is electrogenic, requiring charge compensation to maintain cellular homeostasis. However, the specific mechanism by which H+ ions are transported remained unclear. Established knowledge suggests that H+ efflux is necessary for the function of NADPH oxidase. No prior work had resolved whether a single protein could serve both as an oxidase subunit and an H+ channel. This gap motivated further investigation into the molecular identity of the H+ pathway. The role of gp91phox in this context was not fully understood. Researchers sought to determine if this transmembrane protein could function as the H+ conductance pathway. The need to clarify this mechanism was driven by the potential implications for cellular redox signaling.
Purpose Of The Study:
The authors propose that gp91phox functions as an H+ conductance pathway, enabling charge compensation during superoxide generation.
Histidine 115 in the N-terminal region of gp91phox is important for its ability to conduct H+ ions.
Whole-cell patch clamping was used to record outward currents in CHO91 cells expressing gp91phox.
Voltage-gated H+ currents suggest that gp91phox can function as a voltage-sensitive pathway for H+ efflux.
The aim of this research was to investigate whether the NADPH oxidase subunit gp91phox could act as a proton conductance pathway. The study focused on a stable cell line expressing gp91phox to test its functional role in H+ transport. The researchers sought to determine if gp91phox could mediate H+ flux in a manner consistent with known properties of the NADPH oxidase system. The specific problem addressed was the unresolved identity of the H+ pathway associated with superoxide production. The motivation for this work stemmed from the need to clarify the molecular basis of H+ transport in this system. The study aimed to confirm whether gp91phox could function as both an oxidase subunit and an H+ channel. The researchers also sought to identify specific structural features of gp91phox that are critical for H+ conduction. This work aimed to bridge the gap between functional and structural studies of NADPH oxidase.
Main Methods:
The study used a stable Chinese hamster ovary (CHO) cell line expressing gp91phox. Whole-cell patch clamping was employed to record outward currents associated with H+ flux. The researchers tested the effect of arachidonate and Zn(2+) on H+ transport in these cells. Mutagenesis was performed to assess the role of specific amino acid residues in H+ conduction. Histidine 115 was identified as a key residue in the N-terminal region of gp91phox. The study compared wild-type and mutant forms of gp91phox to determine functional differences. Voltage-gated H+ currents were recorded to assess the conductance properties of the protein. The similarity between voltage-elicited currents and arachidonate-activated H+ flux was analyzed to determine if they represent the same pathway.
Main Results:
The study found that gp91phox is capable of functioning as an H+ conductance pathway. Whole-cell recordings showed outward currents consistent with H+ efflux. Arachidonate activation and Zn(2+) inhibition of H+ flux were observed in CHO91 cells. The N-terminal 230 amino acids of gp91phox were sufficient for H+ channel activity. Histidine 115 was identified as a residue critical for H+ conduction. Voltage-gated H+ currents were recorded, indicating that gp91phox can act as a voltage-sensitive pathway. The similarity between voltage-elicited and arachidonate-activated H+ flux suggests a single pathway. Among gp91phox homologues, only NOH-1S was shown to have similar H+ conductance properties.
Conclusions:
The authors concluded that gp91phox can function as an H+ conductance pathway in NADPH oxidase systems. The data suggest that this protein mediates H+ flux necessary for superoxide production. The N-terminal region of gp91phox is sufficient for H+ channel activity. Histidine 115 is important for the ability of the protein to conduct H+ ions. Voltage-gated H+ currents were observed, supporting the role of gp91phox in this process. The similarity between voltage-elicited and arachidonate-activated H+ flux implies a single pathway. Only NOH-1S among homologues has been shown to act as an H+ conductance pathway. These findings provide insight into the molecular mechanism of H+ transport in NADPH oxidase systems.
Arachidonate activates an H+ pathway that is similar to voltage-elicited currents, suggesting a single H+ conductance mechanism.
Only NOH-1S among gp91phox homologues has been demonstrated to act as an H+ conductance pathway.