The family of ryanodine receptor (RyR) genes encodes three highly related Ca²⁺ release channels: RyR1, RyR2 and RyR3. Until about 10 years ago, RyRs were essentially known for being the Ca²⁺ release channels of the sarcoplasmic reticulum of striated muscles because of the high levels of expression of the RyR1 and RyR2 isoforms in skeletal and cardiac muscles, respectively. In contrast with the above picture, the RyR3 gene has not been found to be preferentially expressed in one specific tissue, but rather to be broadly expressed in different cell types. This broad expression pattern has been subsequently observed also for the RyR1 and RyR2 genes, which in addition to their preferential expression in striated muscles, have been found expressed also in several other cell types. An updated picture reveals therefore that in several cells of vertebrates two or even three RyR isoforms can be co-expressed. This notion has been substantiated by experiments, at a functional level, that suggest that co-expression of different RyR channel isoforms may affect specific aspects of intracellular Ca²⁺ signals and hence modulate the regulation of specific cellular functions.

Further evidence of the biochemical complexity of the mechanisms underlying the process of Ca²⁺ release stems from studies indicating that this process depends, in addition to Ca²⁺ release channels, on the concerted action of a set of proteins, which functionally and physically interact to form a complex ‘molecular machine’. These proteins (i.e. triadin, junctin, homer etc.) appear to play a role in optimising Ca²⁺ release and/or in the organisation of the Ca²⁺ release molecular machinery within specific regions of the cells.

An additional level of complexity of the Ca²⁺ release molecular machinery is provided by the intracellular distribution of Ca²⁺ release channels and associated proteins, which are often organised as distinct functional domains. A better understanding of the functional significance of co-expression of Ca²⁺ release channels and the identification of other components of the Ca²⁺ release molecular machinery as well as studies on how Ca²⁺ release domains are assembled, will certainly contribute to our knowledge of the molecular basis of intracellular Ca²⁺ signalling.

This work was supported by grants from Telethon, MURST, PAR University of Siena and ASI.