IP 3 receptors: An "elementary" journey from structure to signals

• Published in: Cell calcium (Edinburgh) 2023-07, Vol.113, p.102761
• Main Authors: Smith, Holly A, Thillaiappan, Nagendra Babu, Rossi, Ana M
• Format: Article
• Language: English
• Subjects: Calcium - metabolism; Calcium Signaling - physiology; Cytosol - metabolism; Endoplasmic Reticulum - metabolism; Inositol 1,4,5-Trisphosphate - metabolism; Inositol 1,4,5-Trisphosphate Receptors - metabolism
• ISSN: 1532-1991
• DOI: 10.1016/j.ceca.2023.102761

Inositol 1,4,5-trisphosphate receptors (IP Rs) are large tetrameric channels which sit mostly in the membrane of the endoplasmic reticulum (ER) and mediate Ca release from intracellular stores in response to extracellular stimuli in almost all cells. Dual regulation of IP Rs by IP and Ca itself, upstream "licensing", and the arrangement of IP Rs into small clusters in the ER membrane, allow IP Rs to generate spatially and temporally diverse Ca signals. The characteristic biphasic regulation of IP Rs by cytosolic Ca concentration underpins regenerative Ca signals by Ca -induced Ca -release, while also preventing uncontrolled explosive Ca release. In this way, cells can harness a simple ion such as Ca 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 IP R bound to IP and Ca 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 IP Rs and their cellular geography lead to generation of "elementary" local Ca signals known as Ca "puffs", which form the fundamental bottleneck through which all IP -mediated cytosolic Ca signals must first pass.