摘要 : Recently, a functional IP3R ortholog (CO.IP3R-A) capable of IP3-induced Ca2+ release has been discovered in Capsaspora owczarzaki, a close unicellular relative to Metazoa. In contrast to mammalian IP(3)Rs, CO.IP3R-A is not modulat... 展开 Recently, a functional IP3R ortholog (CO.IP3R-A) capable of IP3-induced Ca2+ release has been discovered in Capsaspora owczarzaki, a close unicellular relative to Metazoa. In contrast to mammalian IP(3)Rs, CO.IP3R-A is not modulated by Ca2+, ATP or PKA. Protein-sequence analysis revealed that CO.IP3R-A contained a putative binding site for anti-apoptotic Bcl-2, although Bcl-2 was not detected in Capsaspora owczarzaki and only appeared in Metazoa. Here, we examined whether human Bcl-2 could form a complex with CO.IP3R-A channels and modulate their Ca2+-flux properties using ectopic expression approaches in a HEK293 cell model in which all three IP3R isoforms were knocked out. We demonstrate that human Bcl-2 via its BH4 domain could functionally interact with CO.IP3R-A, thereby suppressing Ca2+ flux through CO.IP3R-A channels. The BH4 domain of Bcl-2 was sufficient for interaction with CO.IP3R-A channels. Moreover, mutating the Lys17 of Bcl-2's BH4 domain, the residue critical for Bcl-2-dependent modulation of mammalian IP 3 Rs, abrogated Bcl-2's ability to bind and inhibit CO.IP3R-A channels. Hence, this raises the possibility that a unicellular ancestor of animals already had an IP3R that harbored a Bcl-2-binding site. Bcl-2 proteins may have evolved as controllers of IP3R function by exploiting this pre-existing site, thereby counteracting Ca2+-dependent apoptosis. 收起