IP₃ receptors: An "elementary" journey from structure to signals

Inositol 1,4,5-trisphosphate receptors (IP₃Rs) are large tetrameric channels which sit mostly in the membrane of the endoplasmic reticulum (ER) and mediate Ca²⁺ release from intracellular stores in response to extracellular stimuli in almost all cells. Dual regulation of IP₃Rs by IP₃ and Ca²⁺ itself, upstream "licensing", and the arrangement of IP₃Rs into small clusters in the ER membrane, allow IP₃Rs to generate spatially and temporally diverse Ca²⁺ signals. The characteristic biphasic regulation of IP₃Rs by cytosolic Ca²⁺ concentration underpins regenerative Ca²⁺ signals by Ca²⁺-induced Ca²⁺-release, while also preventing uncontrolled explosive Ca²⁺ release. In this way, cells can harness a simple ion such as Ca²⁺ as a near-universal intracellular messenger to regulate diverse cellular functions, including those with conflicting outcomes such as cell survival and cell death. High-resolution structures of the IP₃R bound to IP₃ and Ca²⁺ in different combinations have together started to unravel the workings of this giant channel. Here we discuss, in the context of recently published structures, how the tight regulation of IP₃Rs and their cellular geography lead to generation of "elementary" local Ca²⁺ signals known as Ca²⁺ "puffs", which form the fundamental bottleneck through which all IP₃-mediated cytosolic Ca²⁺ signals must first pass.