Calcium (Ca
2+) release from the sarco/endoplasmic reticulum stores generates vital regulatory signals in eukaryotes. The two major groups of Ca
2+ release channels include the ubiquitously expressed inositol 1,4,5-trisphosphate receptors (IP
3Rs) and the ryanodine receptors (RyRs). This review focuses on recently reported structural findings on the N-terminal regions of IP
3Rs and RyRs and their arrangement into full-length tetrameric channels, revealing remarkable mechanistic homologies in Ca
2+-release function. Additionally, we discuss genomic analyses identifying this class of Ca
2+ release channels in unicellular organisms and the implications of these data in understanding the molecular evolution of these fundamental receptors in nature.
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