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Interplay of CRAC channels with Ca2+ activated K+ channels

Interplay of CRAC channels with Ca2+ activated K+ channels

Isabella Derler (ORCID: 0000-0002-4768-146X)
  • Grant DOI 10.55776/P32851
  • Funding program Principal Investigator Projects
  • Status ended
  • Start June 1, 2020
  • End May 31, 2024
  • Funding amount € 399,935
  • Project website
  • E-mail

Disciplines

Biology (100%)

Keywords

    STIM1, Orai1, Ca2+ release activated Ca2+ ion chan

Abstract Final report

Changes in intra- and extracellular ion concentrations are essential in cellular processes and biological functions. Ions are transported across certain pores, the so-called ion channels, within the cell membrane. In this project we aim to improve the understanding how two types of ion channels, a calcium (Ca2+) and a potassium (K+) selective one, interplay with each other and trigger prostate and colon cancer cell growth. A unique Ca2+ entry pathway into living cells represents the so-called Ca2+ release-activated Ca2+ (CRAC) ion channel. Ca2+ entry across this ion pore into the cell regulates a huge diversity of proteins including also Ca2+ activated K+ channels. Defects in those channels or their altered appearance in the human cell can cause among diverse diseases also the development of cancer, highlighting the clinical relevance of those ion pores. Specifically, an interplay of these types of ion channels has been shown to trigger breast, colon and prostate cancer cell growth. However, the detailed molecular determinants underlying the reported co- regulation of Ca2+ and K+ channels have so far remained unresolved and thus, will be clarified throughout this project. For that a combined approach of functional, fluorescence and biochemical studies will be employed to uncover key sites mediating the interplay of those ion channels. Whether a suppression of such key regions impairs the co-regulation of the respective ion channels and in consequence also cancer cell growth will be further investigated. In summary these studies will contribute for to a better understanding of molecular factors contributing to prostate and colon cancer cell growth and provide the basis for the development of novel therapeutic approaches.

Changes in intra- and extracellular ion concentrations are essential in cellular processes and biological functions. Ions are transported across certain pores, the so-called ion channels, within the cell membrane. In this project we aim to improve the understanding how two types of ion channels, a calcium (Ca2+) and a potassium (K+) selective one, interplay with each other and trigger prostate cancer cell growth. A unique Ca2+ entry pathway into living cells represents the so-called Ca2+ release-activated Ca2+ (CRAC) ion channel. Ca2+ entry across this ion pore into the cell regulates a huge diversity of proteins including also Ca2+ activated K+ channels. Defects in those channels or their altered appearance in the human cell can cause among diverse diseases also the development of cancer, highlighting the clinical relevance of those ion pores. Specifically, an interplay of these types of ion channels has been shown to trigger breast, colon and prostate cancer cell growth. However, the detailed molecular conditions for the interaction of these ion channels were unknown until the start of this project. Critical regions and factors that are important for the co-regulation of these ion pores were identified as part of this project. To this end, functional, fluorescence microscopic and biochemical analyses were carried out. Furthermore, it was shown that the interaction of these ion pores is involved in the growth of prostate cancer cells. In summary, our studies will contribute to a better understanding of the molecular factors that contribute to the development of prostate cancer and provide a basis for the development of new therapeutic approaches.

Research institution(s)
  • Medizinische Universität Graz - 5%
  • Universität Linz - 95%
Project participants
  • Klaus Groschner, Medizinische Universität Graz , associated research partner
  • Roland Malli, Medizinische Universität Graz , national collaboration partner
International project participants
  • Mohamed Trebak, University of Pittsburgh - USA

Research Output

  • 183 Citations
  • 27 Publications
  • 5 Policies
  • 1 Datasets & models
  • 1 Disseminations
  • 5 Scientific Awards
  • 3 Fundings
Publications
  • 2023
    Title Activation mechanisms and structural dynamics of STIM proteins
    DOI 10.1113/jp283828
    Type Journal Article
    Author Sallinger M
    Journal The Journal of Physiology
    Pages 1475-1507
    Link Publication
  • 2023
    Title Swing-out opening of stromal interaction molecule 1
    DOI 10.1002/pro.4571
    Type Journal Article
    Author Horvath F
    Journal Protein Science
    Link Publication
  • 2023
    Title Photocrosslinking-induced CRAC channel-like Orai1 activation independent of STIM1
    DOI 10.1038/s41467-023-36458-4
    Type Journal Article
    Author Maltan L
    Journal Nature Communications
    Pages 1286
    Link Publication
  • 2022
    Title CRAC and SK Channels: Their Molecular Mechanisms Associated with Cancer Cell Development
    DOI 10.3390/cancers15010101
    Type Journal Article
    Author Tiffner A
    Journal Cancers
    Pages 101
    Link Publication
  • 2021
    Title Isoform-Specific Properties of Orai Homologues in Activation, Downstream Signaling, Physiology and Pathophysiology
    DOI 10.3390/ijms22158020
    Type Journal Article
    Author Tiffner A
    Journal International Journal of Molecular Sciences
    Pages 8020
    Link Publication
  • 2021
    Title Transmembrane Domain 3 (TM3) Governs Orai1 and Orai3 Pore Opening in an Isoform-Specific Manner
    DOI 10.3389/fcell.2021.635705
    Type Journal Article
    Author Tiffner A
    Journal Frontiers in Cell and Developmental Biology
    Pages 635705
    Link Publication
  • 2022
    Title The Role of Lipids in CRAC Channel Function
    DOI 10.3390/biom12030352
    Type Journal Article
    Author Maltan L
    Journal Biomolecules
    Pages 352
    Link Publication
  • 2020
    Title A series of Orai1 gating checkpoints in transmembrane and cytosolic regions requires clearance for CRAC channel opening: Clearance and synergy of Orai1 gating checkpoints controls pore opening
    DOI 10.1101/2020.07.16.207183
    Type Preprint
    Author Tiffner A
    Pages 2020.07.16.207183
    Link Publication
  • 2020
    Title CRAC channel opening is determined by a series of Orai1 gating checkpoints in the transmembrane and cytosolic regions
    DOI 10.1074/jbc.ra120.015548
    Type Journal Article
    Author Tiffner A
    Journal Journal of Biological Chemistry
    Pages 100224
    Link Publication
  • 2020
    Title Molecular Choreography and Structure of Ca2+ Release-Activated Ca2+ (CRAC) and KCa2+ Channels and Their Relevance in Disease with Special Focus on Cancer
    DOI 10.3390/membranes10120425
    Type Journal Article
    Author Tiffner A
    Journal Membranes
    Pages 425
    Link Publication
  • 2021
    Title Deciphering Molecular Mechanisms and Intervening in Physiological and Pathophysiological Processes of Ca2+ Signaling Mechanisms Using Optogenetic Tools
    DOI 10.3390/cells10123340
    Type Journal Article
    Author Maltan L
    Journal Cells
    Pages 3340
    Link Publication
  • 2021
    Title Orai1 Boosts SK3 Channel Activation
    DOI 10.3390/cancers13246357
    Type Journal Article
    Author Tiffner A
    Journal Cancers
    Pages 6357
    Link Publication
  • 2020
    Title Luminal STIM1 Mutants that Cause Tubular Aggregate Myopathy Promote Autophagic Processes
    DOI 10.3390/ijms21124410
    Type Journal Article
    Author Sallinger M
    Journal International Journal of Molecular Sciences
    Pages 4410
    Link Publication
  • 2020
    Title Blockage of Store-Operated Ca2+ Influx by Synta66 is Mediated by Direct Inhibition of the Ca2+ Selective Orai1 Pore
    DOI 10.3390/cancers12102876
    Type Journal Article
    Author Waldherr L
    Journal Cancers
    Pages 2876
    Link Publication
  • 2024
    Title Insights into the dynamics of the Ca2+ release-activated Ca2+ channel pore-forming complex Orai1
    DOI 10.1042/bst20230815
    Type Journal Article
    Author Fröhlich M
    Journal Biochemical Society Transactions
    Pages 747-760
  • 2024
    Title Synthetic Biology Meets Ca2+ Release-Activated Ca2+ Channel-Dependent Immunomodulation
    DOI 10.3390/cells13060468
    Type Journal Article
    Author Bacsa B
    Journal Cells
    Pages 468
    Link Publication
  • 2024
    Title Genetic code expansion, an emerging tool in the Ca2+ ion channel field
    DOI 10.1113/jp285840
    Type Journal Article
    Author Söllner J
    Journal The Journal of Physiology
    Pages 3297-3313
    Link Publication
  • 2020
    Title Natural photoswitches expose STIM1 activation steps
    DOI 10.1016/j.ceca.2020.102240
    Type Journal Article
    Author Derler I
    Journal Cell Calcium
    Pages 102240
  • 2023
    Title Tubular aggregate myopathy mutant unveils novel activation and inactivation mechanisms of Orai1
    DOI 10.1016/j.ceca.2023.102739
    Type Journal Article
    Author Derler I
    Journal Cell Calcium
    Pages 102739
  • 2023
    Title Analysis of the interplay of the Orai1 Ca2+ ion channel and different Ca2+ sensing proteins
    Type PhD Thesis
    Author Valentina Hopl
  • 2023
    Title Photocrosslinking-induced CRAC channel-like Orai1 activation independent of STIM1
    DOI 10.5281/zenodo.7551826
    Type Journal Article
    Author Maltan Lena
    Link Publication
  • 2023
    Title Photocrosslinking-induced CRAC channel-like Orai1 activation independent of STIM1
    DOI 10.5281/zenodo.7551827
    Type Journal Article
    Author Maltan Lena
    Link Publication
  • 2022
    Title Proteolysis of Orai1 controls cellular Ca2+ influx.
    DOI 10.1016/j.ceca.2022.102535
    Type Journal Article
    Author Derler I
    Journal Cell Calcium
    Pages 102535
  • 2021
    Title Defects in the STIM1 SOARa2 domain affect multiple steps in the CRAC channel activation cascade
    DOI 10.1007/s00018-021-03933-4
    Type Journal Article
    Author Höglinger C
    Journal Cellular and Molecular Life Sciences
    Pages 6645-6667
    Link Publication
  • 2021
    Title Molecular determinants within Orai Ca2+ ion channels essential for their activation
    Type Postdoctoral Thesis
    Author Isabella Derler
  • 2021
    Title The Orai Pore Opening Mechanism.
    DOI 10.3390/ijms22020533
    Type Journal Article
    Author Maltan L
    Journal International journal of molecular sciences
  • 2020
    Title Detailed insights into the regulatory roles of STIM and Orai
    Type PhD Thesis
    Author Adéla Tiffner
Policies
  • 2024
    Title The project stimulates research and project ideas of the PI
    Type Influenced training of practitioners or researchers
  • 2023
    Title The project stimulates research and project ideas on optogenetic ion channel manipulation of Isabella Derler
    Type Influenced training of practitioners or researchers
  • 2023
    Title The project stimulate research and project ideas of the postgraduate Adela Tiffner
    Type Influenced training of practitioners or researchers
  • 2021
    Title Identification and characterization of STIM1 and Orai mutants, which may help to improve our understanding on the interplay of SK3 and Orai
    Type Influenced training of practitioners or researchers
  • 2020
    Title My application and appeal lecture for the professorship "Biophysics" at the University in Graz was ranked at 3rd place.
    Type Influenced training of practitioners or researchers
Datasets & models
  • 2021 Link
    Title Orai1 Boosts SK3 Channel Activation
    Type Database/Collection of data
    Public Access
    Link Link
Disseminations
  • 0
    Title Conference visits
    Type A talk or presentation
Scientific Awards
  • 2024
    Title European Calcium Society Cambridge 2024
    Type Personally asked as a key note speaker to a conference
    Level of Recognition Continental/International
  • 2024
    Title Gordon Research Conference 2024 (Lucca, Italy)
    Type Personally asked as a key note speaker to a conference
    Level of Recognition National (any country)
  • 2023
    Title Meeting of the Austrian Pharmacological Society
    Type Personally asked as a key note speaker to a conference
    Level of Recognition Continental/International
  • 2023
    Title Faseb Meeting 2023, Calcium and Cell Function
    Type Personally asked as a key note speaker to a conference
    Level of Recognition Continental/International
  • 2022
    Title Austrian Biophysical Society Meeting
    Type Personally asked as a key note speaker to a conference
    Level of Recognition National (any country)
Fundings
  • 2020
    Title Interplay of CRAC channels with Ca2+ activated K+ channels
    Type Other
    Start of Funding 2020
    Funder Austrian Science Fund (FWF)
  • 2022
    Title Dynamik des Orai1-Kanals, die die Porenöffnung bestimmt
    Type Research grant (including intramural programme)
    Start of Funding 2022
    Funder Johannes Kepler University of Linz
  • 2023
    Title Neue Einblicke in CRAC-Kanäle durch die Erweiterung des genetischen Codes
    Type Research grant (including intramural programme)
    Start of Funding 2023
    Funder Johannes Kepler University of Linz

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