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Cited by 212Ion Channels and ReceptorsCalcium signaling and nucleotide metabolismIon channel regulation and function

A Homolog of Voltage-Gated Ca 2+ Channels Stimulated by Depletion of Secretory Ca 2+ in Yeast

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Locke, Emily G., Bonilla, Myriam, Liang, Linda, Takita, Yoko, Cunningham, Kyle W.·2000·Molecular and Cellular Biology
DOI 10.1128/mcb.20.18.6686-6694.2000PMC PMC86178
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Abstract

In animal cells, capacitative calcium entry (CCE) mechanisms become activated specifically in response to depletion of calcium ions (Ca(2+)) from secretory organelles. CCE serves to replenish those organelles and to enhance signaling pathways that respond to elevated free Ca(2+) concentrations in the cytoplasm. The mechanism of CCE regulation is not understood because few of its essential components have been identified. We show here for the first time that the budding yeast Saccharomyces cerevisiae employs a CCE-like mechanism to refill Ca(2+) stores within the secretory pathway. Mutants lacking Pmr1p, a conserved Ca(2+) pump in the secretory pathway, exhibit higher rates of Ca(2+) influx relative to wild-type cells due to the stimulation of a high-affinity Ca(2+) uptake system. Stimulation of this Ca(2+) uptake system was blocked in pmr1 mutants by expression of mammalian SERCA pumps. The high-affinity Ca(2+) uptake system was also stimulated in wild-type cells overexpressing vacuolar Ca(2+) transporters that competed with Pmr1p for substrate. A screen for yeast mutants specifically defective in the high-affinity Ca(2+) uptake system revealed two genes, CCH1 and MID1, previously implicated in Ca(2+) influx in response to mating pheromones. Cch1p and Mid1p were localized to the plasma membrane, coimmunoprecipitated from solubilized membranes, and shown to function together within a single pathway that ensures that adequate levels of Ca(2+) are supplied to Pmr1p to sustain secretion and growth. Expression of Cch1p and Mid1p was not affected in pmr1 mutants. The evidence supports the hypothesis that yeast maintains a homeostatic mechanism related to CCE in mammalian cells. The homology between Cch1p and the catalytic subunit of voltage-gated Ca(2+) channels raises the possibility that in some circumstances CCE in animal cells may involve homologs of Cch1p and a conserved regulatory mechanism.

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  • Changes in secretory Ca2+ levels promoted the influx of extracellular 45Ca2+ possibly through CMC in yeast.

    “This notion was reinforced by experiments demonstrating that changes in secretory Ca 2ϩ levels promoted the influx of extracellular 45 Ca 2ϩ possibly through CMC in yeast (20);”

    From Cch1 Restores Intracellular Ca2+ in Fungal Cells during Endoplasmic Reticulum Stress (2010) · cites this paper as [20]

  • C. neoformans survival in low extracellular Ca2+ environments depends on the combined activity of Cch1 and Mid1.

    “Its ability to survive in low [Ca 2ϩ ] environments is dependent on the combined activity of Cch1, the predicted pore of the channel complex, and Mid1, a binding partner of Cch1 (7,14,20).”

    From Cch1 Restores Intracellular Ca2+ in Fungal Cells during Endoplasmic Reticulum Stress (2010) · cites this paper as [20]

  • Electrophysiological evidence supports a Ca2+ depletion gating mechanism for Cch1 and a role for Cch1 in SOC entry in lower eukaryotes.

    “The electrophysiological evidence provided here strongly supports a Ca 2ϩ depletion gating mechanism for Cch1 and further substantiates a role for Cch1 in the process of SOC entry in lower eukaryotes (20).”

    From Cch1 Restores Intracellular Ca2+ in Fungal Cells during Endoplasmic Reticulum Stress (2010) · cites this paper as [20]

  • Cch1-mediated store depletion-activated Ca2+ currents require co-expression of Cch1 and Mid1, i.e., Cch1 activity requires Mid1.

    “Store depletion-mediated inward Ca 2ϩ currents were not detected in HEK cells that expressed either Cch1 or Mid1 alone or an empty plasmid, indicating that the activation of these Ca 2ϩ currents was completely dependent on the co-expression of Cch1 and Mid1 and that Cch1 activity required Mid1, consistent with previous genetic evidence (Fig. 2, F-H) (12,14,20,21).”

    From Cch1 Restores Intracellular Ca2+ in Fungal Cells during Endoplasmic Reticulum Stress (2010) · cites this paper as [20]

  • At about 500 nM free Ca2+, low affinity Ca2+ channels and/or transporters allow Ca2+ influx that supports viable CMC mutants.

    “Lowering [Ca 2ϩ ] further rendered the CMC mutants inviable, but at ϳ500 nM, low affinity Ca 2ϩ channels and/or transporters allow for Ca 2ϩ influx that supports viable CMC mutants (7,20).”

    From Cch1 Restores Intracellular Ca2+ in Fungal Cells during Endoplasmic Reticulum Stress (2010) · cites this paper as [20]

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Authors
Locke, E. G., Bonilla, M., Liang, L., Takita, Y., & Cunningham, K. W.
Affiliations
  • Johns Hopkins University (US)
  • Department of Biology, Johns Hopkins University
Corresponding author
Cunningham, Kyle W.
ORCID
Venue
Molecular and Cellular Biology
Publisher
Informa UK Limited
Published
2000-09
Volume
20
Issue
18
Pages
6686-6694
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
DOI
10.1128/mcb.20.18.6686-6694.2000
PMC
PMC86178
OpenAlex
W2157275644
Cited by
212
References
65
Citations by year
2025: 5 · 2024: 4 · 2023: 1 · 2022: 3 · 2021: 7 · 2020: 5 · 2019: 6 · 2018: 8 · 2017: 11 · 2016: 10 · 2015: 7 · 2014: 9 · 2013: 12 · 2012: 12
FWCI
5.13
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Molecular and Cellular Biology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of General Medical Sciences (GM53083, R01GM053082)
Topics
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
Keywords
store-operated calcium entry, sarcoplasmic reticulum Ca2+-ATPase, calcium homeostasis, Saccharomyces cerevisiae, plasma membrane calcium channels, secretory pathway
MeSH terms
Calcium-Transporting ATPases, Calcium, Fungal Proteins, Membrane Glycoproteins, Saccharomyces cerevisiae, Vacuoles, Calcium Channels, Ion Channel Gating, Mutagenesis, ATP-Binding Cassette Transporters, Molecular Chaperones, Saccharomyces cerevisiae Proteins

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