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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Amcheslavsky, Anna Cahalan, Michael D. Dynes, Joseph L. |
| Description | Author Affiliation: Dynes JL ( Department of Physiology and Biophysics, University of California, Irvine, CA 92697.); Amcheslavsky A ( Department of Physiology and Biophysics, University of California, Irvine, CA 92697.); Cahalan MD ( Department of Physiology and Biophysics, University of California, Irvine, CA 92697 Institute for Immunology, University of California, Irvine, CA 92697 mcahalan@uci.edu.); |
| Abstract | Orai1 comprises the pore-forming subunit of the $Ca^{2+}$ release-activated $Ca^{2+}$ (CRAC) channel. When bound and activated by stromal interacting molecule 1 (STIM1), an endoplasmic reticulum (ER)-resident calcium sensor, Orai1 channels possess high selectivity for calcium but extremely small conductance that has precluded direct recording of single-channel currents. We have developed an approach to visualize Orai1 activity by fusing Orai1 to fluorescent, genetically encoded calcium indicators (GECIs). The GECI–Orai1 probes reveal local $Ca^{2+}$ influx at STIM1–Orai1 puncta. By whole cell recording, these fusions are fully functional as CRAC channels. When GECI–Orai1 and the CRAC-activating domain (CAD) of STIM1 were coexpressed at low levels and imaged using a total internal reflectance fluorescence microscope, cells exhibited sporadic fluorescence transients the size of diffraction-limited spots and the brightness of a few activated GECI proteins. Transients typically rose rapidly and fell into two classes according to duration: briefer “flickers” lasting only a few hundred milliseconds, and longer “pulses” lasting one to several seconds. The size, intensity, trace shape, frequency, distribution, physiological characteristics, and association with CAD binding together demonstrate that GECI–Orai1 fluorescence transients correspond to single-channel Orai1 responses. Single Orai1 channels gated by CAD, and small Orai1 puncta gated by STIM1, exhibit repetitive fluctuations in single-channel output. CAD binding supports a role in open state maintenance and reveals a second phase of CAD/STIM1 binding after channel opening. These first recordings of single-channel Orai1 currents reveal unexpected dynamics, and when paired with CAD association, support multiple single-channel states. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 2 |
| Volume Number | 113 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2016-01-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Calcium Channels Metabolism Calcium Signaling Calcium Ion Channel Gating Optogenetics Chemistry Cell Membrane Fluorescence Green Fluorescent Proteins HEK293 Cells Protein Structure, Tertiary Recombinant Fusion Proteins Time Factors Transfection Research Support, N.I.H., Extramural Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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