Functional determination of calcium-binding sites required for the activation of inositol 1,4,5-trisphosphate receptors

• DOI: 10.1073/pnas.2209267119
• Publication Date: 2022-09-19T19:16:45Z
• Authors: Vikas Arige; Lara E. Terry; Larry E. Wagner; Sundeep Malik; Mariah R. Baker; Guizhen Fan; Suresh K. Joseph; Irina I. Serysheva; David I. Yule
• Keywords: Inositol phosphate; Inositol trisphosphate receptor; Inositol trisphosphate

Inositol 1,4,5-trisphosphate receptors (IP 3 Rs) initiate a diverse array of physiological responses by carefully orchestrating intracellular calcium (Ca 2+ ) signals in response to various external cues. Notably, IP R channel activity is determined several obligatory factors, including , Ca and ATP. The critical basic amino acid residues the N-terminal -binding core (IBC) region that facilitate binding are well characterized. In contrast, conferring regulation have yet be ascertained. Using comparative structural analysis sites identified two main families -release channels, ryanodine (RyRs) Rs, we putative acidic coordinating cytosolic sensor Rs. We consequences substituting binding, family members. show agonist-induced release, single-channel open probability (P 0 ), sensitivities markedly altered when negative charge on conserved side chain neutralized. Remarkably, neutralizing negatively charged individually pocket shifted required activate higher concentrations, indicating these likely component activation site R. Taken together, our findings indicate well-conserved common underlying mechanism resulting increased shared Rs RyRs.