Uncoupled IP3 receptor can function as a Ca^2+ -leak channel: cell biological and pathological consequences

Ca2+ release via intracellular release channels, IP3Rs (inositol 1,4,5-trisphosphate receptors) and RyRs (ryanodine receptors), is perhaps the most ubiquitous and versatile cellular signalling mechanism, and is involved in a vast number of cellular processes. In addition to this classical release pathway there is limited, but yet persistent, information about less well-defined Ca^2+-leak pathways that may play an important role in the control of the Ca^2+ load of the endo(sarco)plasmic reticulum. The mechanisms responsible for this ‘basal’ leak are not known, but recent data suggest that both IP3Rs and RyRs may also operate as Ca^2+-leak channels, particularly in pathological conditions. Proteolytic cleavage or biochemical modification (such as hyperphosphorylation or nitrosylation), for example, occurring during conditions of cell stress or apoptosis, can functionally uncouple the cytoplasmic control domains from the channel domain of the receptor. Highly significant information has been obtained from studies of malfunctioning channels in various disorders; for example, RyRs in cardiac malfunction or genetic muscle diseases and IP3Rs in neurodegenerative diseases. In this review we aim to summarize the existing information about functionally uncoupled IP3R and RyR channels, and to discuss the concept that those channels can participate in Ca^2+-leak pathways.