Papel de las inmunofilinas en la homeostasis del ion calcio en plaquetas humanas

Resumen

Previous publications demonstrated immunophilins regulate the endoplasmic reticulum calcium channels, such a RyR and IP3R. During the present Thesis we aimed to demonstrate the relevance of immunophilins in calcium homeostasis in among others, platelets. General immunophilin antagonist, FK506 impaires calcium release and calcium entry in human platelets. We have confirmed that immunophilins interacted with TRPC1 and Orai1, two key proteins involved in the store-operated calcium entry mechanism (SOCE). We also identified that FKBP52 interacts with TRPC1 for regulating SOCE. Rapamycin inhibits mTOR through interacting with FKBP12, therefore reducing platelet count in kidney transplant patients. Platelet aggregation was also impaired in these patients. Futhermore, rapamycin was shown to reduce granule secretion. On the other hand, in this Thesis we also evidenced that immunophilins regulate Ca2+ homeostasis, platelet secretion and aggregation in patients suffering diabetes mellitus type 2 (DM2), due to FKBP12 and FKBP52 overexpression. In DM2 patients we have reported enhanced TPRC6 permeability; hence, we have also investigated FKBP25 and FKBP38 in TRPC6, which is very relevant for regulating Non Capacitative Ca2+ Entry (NCCE). Our results evidence that immunophilins interact with this channel and subsecuently regulating this mechanism-