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- W3005324814 abstract "Store operated calcium entry (SOCE) is an integral mechanism for calcium signaling and regulation within the cell. SOCE's key players are the Orai channels, calcium selective channel proteins located within the plasma membrane (PM), and the STIM proteins, Ca2+ sensors located within the endoplasmic reticulum (ER) membrane. Upon ER Ca2+ store depletion, STIM proteins form an active conformation that binds to and activates Orai channels. Structural and functional evidence indicate that Orai is allosterically activated by a chain of conformational changes originating from a physical interaction between Orai's C-terminus and STIM1's STIM/Orai activating region (SOAR). Although the mechanism of channel gating is unknown, it is presumed to be conserved amongst all three isoforms of Orai (Orai1, Orai2, Orai3). We chose to investigate Orai3, a less studied SOCE channel subtype shown to be upregulated in hypertrophied cardiomyocytes, and estrogen receptor-expressing breast cancers. To better understand Orai3's activation mechanism, we disrupted different intra-channel points of contact known to be important in Orai1's function using site directed mutagenesis. HEK triple Orai channel-knockout cells were transfected to overexpress our modified Orai3 channels and calcium entry was assessed using fluorescence microscopy. We found that the H109S and P254L mutations in Orai3 caused the channel to be constitutively active, similar to Orai1's corresponding mutations. Recently identified salt bridges connecting transmembrane regions of the protein were found to play an important role in transmitting the STIM1 binding signal to Orai1 channel gating. To test the function of these salt bridges in Orai3, we compared the activity of STIM1 activated channels to the H109S, and P254L constitutively active variants. Our results reveal an important role for the K60/E149 salt bridge in transmitting signals from Orai3's C-terminus to the channel pore." @default.
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- W3005324814 date "2020-02-01" @default.
- W3005324814 modified "2023-09-27" @default.
- W3005324814 title "A Closer Look at Orai3: An Investigation into Constitutively Active Mutants of the Lesser Known Calcium Ion Channel" @default.
- W3005324814 doi "https://doi.org/10.1016/j.bpj.2019.11.2368" @default.
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