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

Calcium homeostasis modulator 1 (CALHM1), a newly discovered voltage-dependent nonselective ion channel, has drawn attention for its role in neuronal activity and taste sensation. Its sluggish voltage-dependent activation is facilitated by lowering extracellular Ca concentration ([Ca ] ). Here, we i...

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Bibliographic Details
Published in:American Journal of Physiology: Cell Physiology 2023-01, Vol.324 (1), p.C98-C112
Main Authors: Kwon, Jae Won, Jeon, Young Keul, Kim, Sung Joon
Format: Article
Language:English
Subjects:
Calcium (extracellular)
Calcium Channels
Calcium channels (voltage-gated)
Calcium homeostasis
Cell Membrane
Depolarization
Excitability
Homeostasis
Humans
Hydrogen-Ion Concentration
Membrane Glycoproteins
Neuromodulation
Neurons
pH effects
Protons
Sensation
Site-directed mutagenesis
Taste
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Summary:Calcium homeostasis modulator 1 (CALHM1), a newly discovered voltage-dependent nonselective ion channel, has drawn attention for its role in neuronal activity and taste sensation. Its sluggish voltage-dependent activation is facilitated by lowering extracellular Ca concentration ([Ca ] ). Here, we investigated the effects of extracellular and intracellular pH (pH and pH ) on human CALHM1. When normalized to the amplitude of the CALHM1 current ( ) under whole cell patch clamp at symmetrical pH 7.4, decreased at acidic pH or pH , whereas it sharply increased at alkaline pH or pH . The effects of pH were preserved in the inside-out configuration. The voltage dependence of showed leftward and rightward shifts at alkaline and acidic pH and pH , 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 nonadditively responsible for facilitation at alkaline pH . Identification of the pH -sensing residue was not possible because mutation of putative residues impaired membrane expression, resulting in undetectable . Alkaline pH -dependent facilitation appeared gradually with depolarization, suggesting that the sensitivity to pH might be due to H diffusion through the open-state CALHM1. At pH 6.2, decreased [Ca ] could not recover the inhibited but further augmented the increased at pH 8.6, suggesting that unidentified common residues might contribute to the [Ca ] and acidic pH . This study is the first, to our knowledge, to demonstrate the remarkable pH sensitivity of CALHM1, which might contribute to the pH-dependent modulation of neuronal excitability or taste sensation.
ISSN:0363-6143
1522-1563
DOI:10.1152/ajpcell.00250.2022