BPS2026 – Regulation of inositol 1,4,5-trisphosphate receptors: Controlling Ca2+ signals in time and space

Inositol 1,4,5-trisphosphate (IP 3 ) receptors (IP 3 Rs) are ubiquitously expressed intracellular calcium (Ca 2+ ) release channels that are predominantly localized to the endoplasmic reticulum. The activation of IP 3 R by its obligate co-agonists IP 3 and Ca 2+ and allosteric tuning by adenosine triphosphate (ATP) regulates IP 3 R activity. Extensive functional data indicate that IP 3 R channel activation occurs following IP 3 binding to the ligand binding domain and Ca 2+ binding to an activation site. Channel inactivation can subsequently occur when higher Ca 2+ are bound to a low affinity Ca 2+ binding motif. This biphasic modulation of IP 3 R activity by Ca 2+ is, in turn, tuned by ATP. In total, this modulation is thought to largely underlie the spatiotemporal characteristics of cellular Ca 2+ signals including Ca 2+ oscillations, Ca 2+ blips, puffs, and waves. Until recently, the motifs responsible for this regulation were unknown; however, near atomic resolution cryo-electron microscopy (cryo-EM) structures of IP 3 Rs have now identified densities corresponding to putative Ca 2+ and ATP-binding domains. Data that provide functional validation of these sites as bone fide motifs responsible for Ca 2+ and ATP regulation of IP 3 Rs will be presented.