Orai1 Boosts SK3 Channel Activation

The interplay of SK3, a Ca sensitive K ion channel, with Orai1, a Ca ion channel, has been reported to increase cytosolic Ca levels, thereby triggering proliferation of breast and colon cancer cells, although a molecular mechanism has remained elusive to date. We show in the current study, via heter...

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Bibliographic Details
Published in:Cancers 2021-12, Vol.13 (24), p.6357
Main Authors: Tiffner, Adéla, Hopl, Valentina, Schober, Romana, Sallinger, Matthias, Grabmayr, Herwig, Höglinger, Carmen, Fahrner, Marc, Lunz, Victoria, Maltan, Lena, Frischauf, Irene, Krivic, Denis, Bhardwaj, Rajesh, Schindl, Rainer, Hediger, Matthias A, Derler, Isabella
Format: Article
Language:English
Subjects:
Breast cancer
Calcium channels
Calcium influx
Calcium-binding protein
Calmodulin
Cell growth
Cell proliferation
Channel gating
Cloning
Colon cancer
Colorectal cancer
CRISPR
Drug development
Ion channels
Kinases
Laboratories
Localization
Mutagenesis
Mutation
Orai1 protein
Physiology
Potassium
Potassium channels (calcium-gated)
Potassium currents
Prostate cancer
Research parks
Signal transduction
STIM1 protein
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Summary:The interplay of SK3, a Ca sensitive K ion channel, with Orai1, a Ca ion channel, has been reported to increase cytosolic Ca levels, thereby triggering proliferation of breast and colon cancer cells, although a molecular mechanism has remained elusive to date. We show in the current study, via heterologous protein expression, that Orai1 can enhance SK3 K currents, in addition to constitutively bound calmodulin (CaM). At low cytosolic Ca levels that decrease SK3 K permeation, co-expressed Orai1 potentiates SK3 currents. This positive feedback mechanism of SK3 and Orai1 is enabled by their close co-localization. Remarkably, we discovered that loss of SK3 channel activity due to overexpressed CaM mutants could be restored by Orai1, likely via its interplay with the SK3-CaM binding site. Mapping for interaction sites within Orai1, we identified that the cytosolic strands and pore residues are critical for a functional communication with SK3. Moreover, STIM1 has a bimodal role in SK3-Orai1 regulation. Under physiological ionic conditions, STIM1 is able to impede SK3-Orai1 interplay by significantly decreasing their co-localization. Forced STIM1-Orai1 activity and associated Ca influx promote SK3 K currents. The dynamic regulation of Orai1 to boost endogenous SK3 channels was also determined in the human prostate cancer cell line LNCaP.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers13246357