Toward a high-resolution structure of IP3R channel

The ability of cells to maintain low levels of Ca2+ under resting conditions and to create rapid and transient increases in Ca2+ upon stimulation is a fundamental property of cellular Ca2+ signaling mechanism. An increase of cytosolic Ca2+ level in response to diverse stimuli is largely accounted for by the inositol 1,4,5-trisphosphate receptor (IP3R) present in the endoplasmic reticulum membranes of virtually all eukaryotic cells. Extensive information is currently available on the function of IP(3)Rs and their interaction with modulators. Very little, however, is known about their molecular architecture and therefore most critical issues surrounding gating of IP3R channels are still ambiguous, including the central question of how opening of the IP3R pore is initiated by IP3 and Ca2+. Membrane proteins such as IP3R channels have proven to be exceptionally difficult targets for structural analysis due to their large size, their location in the membrane environment, and their dynamic nature. To date, a 3D structure of complete IP3R channel is determined by single-particle cryo-EM at intermediate resolution, and the best crystal structures of IP3R are limited to a soluble portion of the cytoplasmic region representing similar to 15% of the entire channel protein. Together these efforts provide the important structural information for this class of ion channels and serve as the basis for further studies aiming at understanding of the IP3R function. (C) 2014 Elsevier Ltd. All rights reserved.