From IP3RPEP6 Inhibition of IP₃ receptor channels to insights: do channel subunits collaborate or cooperate?

Inositol 1,4,5-trisphosphate (IP₃) receptor channels are intracellular ion channels activated by IP₃ and provoking Ca²⁺ release from ER/SR stores, playing fundamental roles in various cell functions ranging from fertilization up to cell death control. The channels are tetrameric structures centered around a Ca²⁺-permeable pore, which mutually interact to control channel opening initiated by both IP₃ and cytoplasmic Ca²⁺. IP₃ receptor (IP3R) channels come in 3 distinct subtypes with cryo-EM data currently being available for IP3R1 and IP3R3. These studies have demonstrated that IP₃ association with the IP₃ binding core (IBC) of a given subunit, triggers retraction of the ARM2 domain in a neighbor subunit, leading to IP₃ capture by the IBC of the initiating subunit, demonstrating subunit collaboration. ARM2 of IP3R2/3 contains a self-binding peptide that associates with the IBC but becomes displaced upon ARM2 retraction, thereby uncovering the IBC of a neighbor subunit, facilitating IP₃ access and thus potentially providing subunit cooperation. Distinct from collaboration, subunit cooperation has the potential to be forwarded across all 4 subunits. We here provide novel insight and understanding on the role of both IP₃ and Ca²⁺ in the steeply negative Hill behavior observed for IP3R inhibition by IP3RPEP6, a self-binding peptide derived from the ARM2 domain. In this light, we discuss the broad variety of reported IP3R Hill slopes and conclude that subunit cooperation operates at both activation and inhibition levels, suggesting adaptability to the cell state to either provide a well-titrated or an all-or-nothing response depending on the conditions and necessity.