Understanding the Role of IP₃ Receptor Subtypes in Calcium Signaling♦

♦ See referenced article, J. Biol. Chem. 2013, 288, 29772–29784

Vertebrates express three subtypes of the inositol 1,4,5-trisphosphate (IP₃) receptor: IP₃R1, IP₃R2, and IP₃R3, which are ubiquitous intracellular Ca²⁺ release channels. These subtypes assemble into homo- and heterotetrameric channels. The activities of IP₃R subtypes are differentially regulated by IP₃, calcium ions, ATP, and other factors that help define the characteristics of the intracellular Ca²⁺ signal. However, details of how the different subunits work together in heterotetrameric channels have been challenging to understand because it is difficult to define in vivo the constituent monomers of the tetrameric channels. In this Paper of the Week, a team led by David I. Yule at the University of Rochester in New York expressed concatenated IP₃R dimers connected by short flexible linkers in a cell line missing IP₃R. The investigators showed that these constructs were able to form fully functional channels and had the same properties as channels made from monomeric proteins. Furthermore, heterotetrameric channels containing IP₃R1 and IP₃R2 behaved much like homotetrameric channels of IP₃R2. The authors concluded, “Importantly, the results indicate that the properties of these channels are not simply a blend of those of the constituent IP₃R monomers.” This property likely adds a further layer of fine-tuning controlling the activity of IP₃R.

Robust IP₃-mediated Ca²⁺ release activity in cells expressing dimeric IP₃R constructs.