Intramolecular Disulfide Bonds for Biogenesis of CALHM1 Ion Channel Are Dispensable for Voltage-Dependent Activation

Kwon, Jae Won; Jeon, Young Keul; Kim, Jin-Sung; Kim, Sang Jeong; Kim, Sung Joon

doi:10.14348/molcells.2021.0131

Cited by 3 publications

(1 citation statement)

References 48 publications

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“…Under non‐denaturing conditions, CALHM6 resolves around 720 kDa, suggesting that endogenous CALHM6 is part of a larger complex in BMDM, significantly larger than the CALHM1 complex, which contains eight subunits. As disulphide bonds in the inter‐helix loop are important for the integrity of other CALHM channels (Siebert et al , 2013 ; Yang et al , 2020 ; Kwon et al , 2021 ), we tested if this was true for CALHM6 as well, by resolving the non‐reduced protein by SDS–PAGE with increasing concentrations of DTT (Fig 6B ). Like in CALHM1, the presence of a reducing agent broke down the CALHM6 complex to its monomeric constituents.…”

Section: Resultsmentioning

confidence: 99%

The ion channel CALHM6 controls bacterial infection‐induced cellular cross‐talk at the immunological synapse

Danielli

Pantazi

et al. 2023

The EMBO Journal

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Membrane ion channels of the calcium homeostasis modulator (CALHM) family promote cell–cell crosstalk at neuronal synapses via ATP release, where ATP acts as a neurotransmitter. CALHM6, the only CALHM highly expressed in immune cells, has been linked to the induction of natural killer (NK) cell anti‐tumour activity. However, its mechanism of action and broader functions in the immune system remain unclear. Here, we generated Calhm6−/− mice and report that CALHM6 is important for the regulation of the early innate control of Listeria monocytogenes infection in vivo. We find that CALHM6 is upregulated in macrophages by pathogen‐derived signals and that it relocates from the intracellular compartment to the macrophage‐NK cell synapse, facilitating ATP release and controlling the kinetics of NK cell activation. Anti‐inflammatory cytokines terminate CALHM6 expression. CALHM6 forms an ion channel when expressed in the plasma membrane of Xenopus oocytes, where channel opening is controlled by a conserved acidic residue, E119. In mammalian cells, CALHM6 is localised to intracellular compartments. Our results contribute to the understanding of neurotransmitter‐like signal exchange between immune cells that fine‐tunes the timing of innate immune responses.

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Section: Resultsmentioning

confidence: 99%

The ion channel CALHM6 controls bacterial infection‐induced cellular cross‐talk at the immunological synapse

Danielli

Pantazi

et al. 2023

The EMBO Journal

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Calcium homeostasis modulator 2 (Calhm2) as slowly activating membrane current channel in mouse B cells

Choi,

Kwon,

Kang

et al. 2024

Biochemical and Biophysical Research Communications

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Bidirectional sensitivity of CALHM1 channel to protons from both sides of plasma membrane

Kwon

Jeon

Kim

2023

American Journal of Physiology-Cell Physiology

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Calcium homeostasis modulator 1 (CALHM1), a newly discovered voltage-dependent nonselective ion channel, has drawn attention to its role in neuronal activity and taste sensation. Its sluggish voltage-dependent activation is facilitated by lowering extracellular Ca2+ concentration ([Ca2+]e). Here, we investigated the effects of extracellular and intracellular pH (pHe and pHi) on human CALHM1. When normalized to the amplitude of the CALHM1 current (ICALHM1) under whole-cell patch clamp at symmetrical pH 7.4, ICALHM1 decreased at acidic pHe or pHi, whereas it sharply increased at alkaline pHe or pHi. The effects of pH were preserved in the inside-out configuration. The voltage dependence of ICALHM1 showed leftward and rightward shifts at alkaline and acidic pHe and pHi, respectively. Site-directed mutagenesis of the water-accessible charged residues of the pore and nearby domains revealed that E17, K229, E233, D257, and E259 are non-additively responsible for facilitation at alkaline pHi. Identification of the pHe-sensing residue was not possible because mutation of putative residues impaired membrane expression, resulting in undetectable ICALHM1. Alkaline pHe-dependent facilitation, but not inhibition at acidic pHe, was use-dependent, suggesting that the sensitivity to pHe could be due to H+ diffusion through the open-state CALHM1. At pHe 6.2, decreased [Ca2+]e could not recover the inhibited ICALHM1 but further augmented the increased ICALHM1 at pHe 8.6, suggesting that unidentified common residues might contribute to the [Ca2+]e and acidic pHe. This study is the first to demonstrated the remarkable pH-sensitivity of CALHM1, which might be responsible for the pH-dependent modulation of neuronal excitability or taste sensation.

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Intramolecular Disulfide Bonds for Biogenesis of CALHM1 Ion Channel Are Dispensable for Voltage-Dependent Activation

Cited by 3 publications

References 48 publications

The ion channel CALHM6 controls bacterial infection‐induced cellular cross‐talk at the immunological synapse

The ion channel CALHM6 controls bacterial infection‐induced cellular cross‐talk at the immunological synapse

Calcium homeostasis modulator 2 (Calhm2) as slowly activating membrane current channel in mouse B cells

Bidirectional sensitivity of CALHM1 channel to protons from both sides of plasma membrane

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