Curling the curl in coincidence detection

The inositol-1,4,5-trisphosphate (Ins(1,4,5)P₃) receptor (InsP₃R) is a calcium channel of the endoplasmic reticulum. It is well known that this channel opens in response to Ins(1,4,5)P₃ and calcium, but new data indicate that signalling through this pathway might be more complex than we previously thought; Yang et al. have identified a family of proteins that can directly activate the channel in the absence of Ins(1,4,5)P₃.

The authors looked for proteins that bind to the InsP₃R and singled out a group of molecules that are known as calcium-binding proteins (CaBPs). CaBPs belong to a larger family of proteins known as neuronal calcium-binding proteins, which includes molecules such as recoverin, frequenin and calsenilin. Yang et al. found that CaBPs interact with the three different isoforms of the InsP₃R, and that the interaction depends on the ability of the CaBPs to bind calcium. Crucially, binding of the CaBPs to the InsP₃R led to channel opening in the absence of Ins(1,4,5)P₃, indicating that CaBPs can act as ligands of this receptor. They also showed co-localization of CaBPs and the InsP₃R, and obtained evidence that the two proteins interact in brain lysates.

InsP₃R channel opening requires both Ins(1,4,5)P₃ and calcium. For this reason, this molecule has been thought of as a coincidence detector that can sense the activation of separate synaptic inputs that might independently increase the levels of those two small signalling molecules. The data of Yang et al. complicate this view because they raise the possibility that the InsP₃R is activated simply as the result of an elevation in calcium. As coincidence detection by the InsP₃R has been invoked, in particular, to explain cerebellar long-term depression, Purkinje cells might be a good system in which to explore the implications of the new findings.