Mechanism of capacitative Ca2+ entry (CCE): interaction between IP3 receptor and TRP links the internal calcium storage compartment to plasma membrane CCE channels.

Activation of cells by agents that stimulate inositol trisphoshate (IP3) formation causes, via IP3 receptor (IP3R) activation, the release of Ca2+ from internal stores and also the entry of Ca2+ via plasma membrane cation channels, referred to as capacitative Ca2+ entry or CCE channels. Trp proteins have been proposed to be the unitary subunits forming CCE channels; however, there is no definitive proof for this hypothesis. We have now identified amino acid sequences of a Trp and of an IP3R that interact to form stable complexes. These complexes appear to form in vivo, as evidenced by co-immunoprecipitation of Trp with IP3R and by the fact that expression of the respective interacting sequences modulates development of CCE brought about by store depletion. The finding that a Trp-interacting sequence of IP3R interferes with natural CCE leads us to conclude that Trp proteins are, indeed, structural members of CCE channels. We conclude further that direct coupling of IP3R to Trp is a physiological mechanism by which cells trigger CCE in response to signals that stimulate phosphoinositide hydrolysis and IP3 formation. Pros and cons of various CCE activation models are discussed.