Abstract
Inositol (1,4,5)-trisphosphate receptors (InsP3R) are the predominant route of Ca2+ release in non-excitable cells and they play a vital role in regulating intracellular Ca2+ signals. There are three isoforms (InsP3R-1, InsP3R-2 and InsP3R-3) of InsP3R expressed in mammalian cells. This sequence diversity along with varied tissue distributions suggests that there are isoform-specific regulatory mechanisms. One such regulatory mechanism is the modulation of Ca2+ release from InsP3R by cytosolic ATP. ATP positively regulates all three InsP3R isoforms, but with distinct functional characteristics. We found that ATP was required for maximal InsP3-induced Ca2+ release from InsP3R-1 and InsP3R-3 while InsP3R-2 attained maximal activity in the absence of ATP. Furthermore, InsP3R-2 was more sensitive to ATP modulation than either InsP3R-1 or InsP3R-3. All three isoforms contain putative ATP binding domains, but the contributions of these sites to ATP modulation of InsP3R are poorly understood. InsP3R-1 contains two predicted ATP binding domains (ATPA, and ATPB) while InsP3R-2 and InsP3R-3 each express a single ATPB site. We examined the contributions of these ATP binding sites to the subtype-specific effects of ATP on InsP3R isoforms. ER Ca2+ measurements from permeabilized DT40 cells and single channel recordings of InsP3R were used to measure the effects of ATP on wild-type and mutated InsP3R. We found that ablation of the ATPB site in InsP3R-2 eliminated the enhancing effects of ATP on this isoform. Surprisingly, the positive effects of ATP were retained in InsP3R-1 and InsP3R-3 devoid of their respective ATP binding sites. ATP, therefore, differentially regulates the three InsP3R isoforms and likely regulates InsP3R-1 and InsP3R-3 via novel ATP binding sites. The implications of this differential regulation on Ca2+ signals would likely be determined by the relative ratios of the three isoforms expressed in a given cell.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
