Inhibiting Hv1 channel in peripheral sensory neurons attenuates chronic inflammatory pain and opioid side effects

Zhang, Qiansen; Ren, Yimin; Mo, Yiqing; Guo, Peipei; Liao, Ping; Luo, Yuncheng; Mei, Jie; Chen, Zhuo; Zhang, Yang; Li, Ya; Yang, Linghui; Liao, Daqing; Fu, Jie; Shen, Ji; Huang, Wei; Xu, Xuewen; Guo, Yanyan; Mei, Lianghe; Zuo, Yunxia; Liu, Jin; Yang, Huaiyu; Jiang, Ruotian

doi:10.1038/s41422-022-00616-y

Cited by 31 publications

(31 citation statements)

References 88 publications

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“…In such experimental conditions, HEK293 cells transfected with the mutant R223A or R230A showed measurable currents under control conditions, while the mutant S97A failed to show any measurable current. Although there are reports where the current mediated by the mutant S97A of hHv1 was recorded, those experiments were performed in the WC configuration and under asymmetrical pH conditions, , which is not suitable for our experimental design. As shown in Figure , 3 mM ATP was able to activate the hHv1 mutant R230A (3.08 ± 0.59 fold over control at +40 mV, n = 7, p < 0.05) in a similar magnitude compared to the WT channel.…”

Section: Resultsmentioning

confidence: 99%

Novel Dimeric hHv1 Model and Structural Bioinformatic Analysis Reveal an ATP-Binding Site Resulting in a Channel Activating Effect

Llanos

Ventura

Martín

et al. 2022

J. Chem. Inf. Model.

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The human voltage-gated proton channel (hHv1) is a highly selective ion channel codified by the HVCN1 gene. It plays a fundamental role in several physiological processes such as innate and adaptive immunity, insulin secretion, and sperm capacitation. Moreover, in humans, a higher hHv1 expression/function has been reported in several types of cancer cells. Here we report a multitemplate homology model of the hHv1 channel, built and refined as a dimer in Rosetta. The model was then subjected to extensive Gaussian accelerated molecular dynamics (GaMD) for enhanced conformational sampling, and representative snapshots were extracted by clustering analysis. Combining different structure-and sequence-based methodologies, we predicted a putative ATP-binding site located on the intracellular portion of the channel. Furthermore, GaMD simulations of the ATP-bound dimeric hHv1 model showed that ATP interacts with a cluster of positively charged residues from the cytoplasmic N and C terminal segments. According to the in silico predictions, we found that 3 mM intracellular ATP significantly increases the H + current mediated by the hHv1 channel expressed in HEK293 cells and measured by the patch-clamp technique in an inside-out configuration (2.86 ± 0.63 fold over control at +40 mV). When ATP was added on the extracellular side, it was not able to activate the channel supporting the idea that the ATP-binding site resides in the intracellular face of the hHV1 channel. In a physiological and pathophysiological context, this ATP-mediated modulation could integrate the cell metabolic state with the H + efflux, especially in cells where hHv1 channels are relevant for pH regulation, such as pancreatic β-cells, immune cells, and cancer cells.

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Section: Resultsmentioning

confidence: 99%

Novel Dimeric hHv1 Model and Structural Bioinformatic Analysis Reveal an ATP-Binding Site Resulting in a Channel Activating Effect

Llanos

Ventura

Martín

et al. 2022

J. Chem. Inf. Model.

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“…The importance of blocking the channel at positive potentials is clear when considering neutrophils that depolarize during the inflammatory respiratory burst to +58 mV ( 17 ), a voltage where monomeric C6 has low affinity. C6 2 offers a powerful tool for basic studies of hHv1 and serves with the state-dependent blocker C6 as a lead for studying treatment of diseases where the channel contributes to pathology, including pulmonary damage by leukocytes in pneumonia and acute respiratory distress syndrome (an inflammatory lung disease that is lethal in 40% of patients) ( 18 ), ischemic stroke ( 19 ), cancer ( 20 ), and both neuropathic and inflammatory pain ( 21 , 22 ).…”

mentioning

confidence: 99%

Molecular determinants of inhibition of the human proton channel hHv1 by the designer peptide C6 and a bivalent derivative

Zhao

Shen

Dai

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Significance We designed C6 peptide to address the absence of specific inhibitors of human voltage-gated proton channels (hHv1). Two C6 bind to the two hHv1 voltage sensors at the resting state, inhibiting activation on depolarization. Here, we identify the C6–hHv1 binding interface using tethered-toxin variants and channel mutants, unveil an important role for negatively charged lipids, and present a model of the C6–hHv1 complex. Inspired by nature, we create a peptide with two C6 epitopes (C6 2 ) that binds to both channel subunits simultaneously, yielding picomolar affinity and significantly improved inhibition at high potentials. C6 and C6 2 are peptides designed to regulate hHv1, a channel involved in innate immune-system inflammatory pathophysiology, sperm capacitation, cancer-cell proliferation, and tissue damage in ischemic stroke.

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“…Finally, it ranks each candidate pocket by its predicted ability to bind small molecules. Of note, fpocket has been recently used in projects focused on druggable SARS-CoV-2 RNA structural elements [ 32 ], AT1-receptor allosteric sites [ 33 ], and Hv1-channel inhibitors [ 34 ].…”

Section: Examples Of Cadd Browser Appsmentioning

confidence: 99%

Open-Source Browser-Based Tools for Structure-Based Computer-Aided Drug Discovery

Wang

Durrant

2022

Molecules

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We here outline the importance of open-source, accessible tools for computer-aided drug discovery (CADD). We begin with a discussion of drug discovery in general to provide context for a subsequent discussion of structure-based CADD applied to small-molecule ligand discovery. Next, we identify usability challenges common to many open-source CADD tools. To address these challenges, we propose a browser-based approach to CADD tool deployment in which CADD calculations run in modern web browsers on users’ local computers. The browser app approach eliminates the need for user-initiated download and installation, ensures broad operating system compatibility, enables easy updates, and provides a user-friendly graphical user interface. Unlike server apps—which run calculations “in the cloud” rather than on users’ local computers—browser apps do not require users to upload proprietary information to a third-party (remote) server. They also eliminate the need for the difficult-to-maintain computer infrastructure required to run user-initiated calculations remotely. We conclude by describing some CADD browser apps developed in our lab, which illustrate the utility of this approach. Aside from introducing readers to these specific tools, we are hopeful that this review highlights the need for additional browser-compatible, user-friendly CADD software.

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Inhibiting Hv1 channel in peripheral sensory neurons attenuates chronic inflammatory pain and opioid side effects

Cited by 31 publications

References 88 publications

Novel Dimeric hHv1 Model and Structural Bioinformatic Analysis Reveal an ATP-Binding Site Resulting in a Channel Activating Effect

Novel Dimeric hHv1 Model and Structural Bioinformatic Analysis Reveal an ATP-Binding Site Resulting in a Channel Activating Effect

Molecular determinants of inhibition of the human proton channel hHv1 by the designer peptide C6 and a bivalent derivative

Open-Source Browser-Based Tools for Structure-Based Computer-Aided Drug Discovery

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