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Cited by 76Fungal Infections and StudiesIon channel regulation and functionFungal and yeast genetics research

Cch1 Mediates Calcium Entry in Cryptococcus neoformans and Is Essential in Low-Calcium Environments

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Liu, Min, Du, Ping, Heinrich, Garrett, Cox, Gary M., Gelli, Angie·2006·Eukaryotic Cell
DOI 10.1128/ec.00158-06PMC PMC1595334
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Abstract

The ability of Cryptococcus neoformans to grow at the mammalian body temperature (37°C to 39°C) is a well-established virulence factor. Growth of C. neoformans at this physiological temperature requires calcineurin, a Ca 2+ /calmodulin-dependent protein phosphatase. When cytosolic calcium concentrations are low (∼50 to 100 nM), calcineurin is inactive and becomes active only when cytosolic calcium concentrations rise (∼1 to 10 μM) through the activation of calcium channels. In this study we analyzed the function of Cch1 in C. neoformans and found that Cch1 is a Ca 2+ -permeable channel that mediates calcium entry in C. neoformans . Analysis of the Cch1 protein sequence revealed differences in the voltage sensor (S4 regions), suggesting that Cch1 may have diminished voltage sensitivity or possibly an alternative gating mechanism. The inability of the cch1 mutant to grow under conditions of limited extracellular calcium concentrations ([Ca 2+ ] extracellular , ∼100 nM) suggested that Cch1 was required for calcium uptake in low-calcium environments. These results are consistent with the role of ScCch1 in mediating high-affinity calcium uptake in Saccharomyces cerevisiae . Although the growth defect of the cch1 mutant under conditions of limited [Ca 2+ ] extracellular (∼100 nM) became more severe with increasing temperature (25°C to 38.5°), this temperature sensitivity was not observed when the cch1 mutant was grown on rich medium ([Ca 2+ ] extracellular , ∼0.140 mM). Accordingly, the cch1 mutant strain displayed only attenuated virulence when tested in the mouse inhalation model of cryptococcosis, further suggesting that C. neoformans may have a limited requirement for Cch1 and that this requirement appears to include ion stress tolerance.

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  • Strains of C. neoformans lacking CCH1 or MID1 were not viable in conditions of limiting extracellular Ca2+.

    “Genetic analysis has indicated that strains of C. neoformans lacking CCH1 or MID1 were not viable in conditions of limiting extracellular [Ca 2ϩ ], consistent with its role as the only high affinity Ca 2ϩ channel in the plasma membrane (7,14).”

    From Cch1 Restores Intracellular Ca2+ in Fungal Cells during Endoplasmic Reticulum Stress (2010) · cites this paper as [7]

  • Cch1 is the only high affinity Ca2+ channel in the plasma membrane of C. neoformans.

    “Genetic analysis has indicated that strains of C. neoformans lacking CCH1 or MID1 were not viable in conditions of limiting extracellular [Ca 2ϩ ], consistent with its role as the only high affinity Ca 2ϩ channel in the plasma membrane (7,14).”

    From Cch1 Restores Intracellular Ca2+ in Fungal Cells during Endoplasmic Reticulum Stress (2010) · cites this paper as [7]

  • 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 [7]

  • 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 [7]

  • Cch1 is not voltage-gated, supported by previous findings that Cch1 in C. neoformans lacks the conserved voltage sensor motif.

    “Our results indicate that Cch1 is not voltage-gated, and this is further supported by our previous findings demonstrating that the protein sequence of Cch1 in C. neoformans lacks the highly conserved voltage sensor motif, the hallmark of all voltage-gated channels in eukaryotic cells (7,(35)(36)(37).”

    From Cch1 Restores Intracellular Ca2+ in Fungal Cells during Endoplasmic Reticulum Stress (2010) · cites this paper as [7]

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Authors
Liu, M., Du, P., Heinrich, G., Cox, G. M., & Gelli, A.
Affiliations
  • University of California, Davis (US)
  • Duke Medical Center (US)
Corresponding author
Gelli, Angie
ORCID
Venue
Eukaryotic Cell
Publisher
American Society for Microbiology
Published
2006-10
Volume
5
Issue
10
Pages
1788-1796
ISSN
  • 1535-9778 (ISSN-L)
  • 1535-9786
DOI
10.1128/ec.00158-06
PMC
PMC1595334
OpenAlex
W2149908761
Semantic Scholar
bab59a19da936ccee4af53f2af9f5fb534a859a2
Cited by
76
References
50
Citations by year
2026: 5 · 2025: 3 · 2024: 2 · 2023: 1 · 2022: 1 · 2021: 4 · 2020: 3 · 2019: 3 · 2018: 4 · 2017: 4 · 2016: 4 · 2015: 3 · 2014: 8 · 2013: 5 · 2012: 7
FWCI
3.19
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Eukaryotic Cell (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Allergy and Infectious Diseases (R01 AI54477, R01AI054477, AI 39156, U01AI039156)
Topics
  • Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Keywords
calcium channels, calcium influx, Cryptococcus neoformans, calcineurin, temperature sensitivity, virulence, cryptococcosis
MeSH terms
Amino Acid Sequence, Animals, Inhalation, Calcium, Cell Wall, Cryptococcosis, Cryptococcus neoformans, Disease Models, Animal, Eukaryotic Cells, Fungal Proteins, Lithium, Molecular Sequence Data, Saccharomyces cerevisiae, Temperature, Virulence, Sequence Alignment, Calcium Channels, L-Type, Mutant Proteins, Mice

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