Highly Ca2+ selective channels trigger a large variety of cellular signaling processes in both excitable and non-excitable cells. Among these channels, the Orai channel is unique in its activation mechanism and its structure. It mediates Ca2+ influx into the cytosol with an extremely small unitary conductance over longer time-scales, ranging from minutes up to several hours. Its activation is regulated by the Ca2+ content of the endoplasmic reticulum (ER). Depletion of luminal [Ca2+]ER is sensed by the STIM1 single transmembrane protein that directly binds and gates the Orai1 channel. Orai mediated Ca2+ influx increases cytosolic Ca2+ from 100 nM up to low micromolar range close to the pore and thereby forms Ca2+ microdomains. Hence, these features of the Orai channel can trigger long-term signaling processes without affecting the overall Ca2+ content of a single living cell. Here we focus on the architecture and dynamic conformational changes within the Orai channel. This review summarizes current achievements of molecular dynamics simulations in combination with live cell recordings to address gating and permeation of the Orai channel with molecular precision.

Center for Nanobiology and Structural Biology Institute of Microbiology Academy of Sciences of the Czech Republic Nové Hrady CZ 373 33 Czech Republic

Center for Nanobiology and Structural Biology Institute of Microbiology Academy of Sciences of the Czech Republic Nové Hrady CZ 373 33 Czech Republic; College of Biomedical Sciences Larkin University Miami FL 33169 United States

Gottfried Schatz Research Center Medical University of Graz A 8010 Graz Austria

Institute for Biophysics Johannes Kepler University Linz A 4040 Linz Austria

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