Store-operated Ca2+ entry channels: still elusive!

Depletion of intracellular Ca2+ stores is believed to trigger Ca2+ entry through a Ca2+- permeable channel in the plasma membrane called the store-operated Ca2+ channel (SOC). This type of Ca2+ entry is thought to play a pivotal role in a plethora of cell functions ranging from gene expression to sensory signal transduction. However, the molecular nature of these channels is still elusive. Many molecular candidates have been described as SOCs, but the candidacy of each has been countered by reports indicating that they are not SOCs. Most of the suggested candidates are members of the recently discovered superfamily of transient receptor potential cation channels (TRPCs). However, no TRP-family channel has yet been incontestably identified as an SOC. Even for the electrophysiologically best-described SOC, the highly Ca2+-permeable channel Ca2+ release-activated Ca2+ channel (CRAC), an acceptable candidate has yet to emerge. This perspective summarizes problems in identifying SOCs, suggests approaches to solving these problems, and discusses concerns over the current tendency to focus exclusively on the hypothesis that TRPCs comprise SOCs.