title: Selective modulation of subtype III IP₃R by Akt regulates ER Ca²⁺ release and apoptosis.
abstract: Ca²⁺ transfer from endoplasmic reticulum (ER) to mitochondria can trigger apoptotic pathways by inducing release of mitochondrial pro-apoptotic factors. Three different types of inositol 1,4,5-trisphosphate receptor (IP₃R) serve to discharge Ca²⁺ from ER, but possess some peculiarities, especially in apoptosis induction. The anti-apoptotic protein Akt can phosphorylate all IP₃R isoforms and protect cells from apoptosis, reducing ER Ca²⁺ release. However, it has not been elucidated which IP₃R subtypes mediate these effects. Here, we show that Akt activation in COS7 cells, which lack of IP₃R I, strongly suppresses IP₃-mediated Ca²⁺ release and apoptosis. Conversely, in SH-SY 5Y cells, which are type III-deficient, Akt is unable to modulate ER Ca²⁺ flux, losing its anti-apoptotic activity. In SH-SY 5Y-expressing subtype III, Akt recovers its protective function on cell death, by reduction of Ca²⁺ release. Moreover, regulating Ca²⁺ flux to mitochondria, Akt maintains the mitochondrial integrity and delays the trigger of apoptosis, in a type III-dependent mechanism. These results demonstrate a specific activity of Akt on IP₃R III, leading to diminished Ca²⁺ transfer to mitochondria and protection from apoptosis, suggesting an additional level of cell death regulation mediated by Akt.
authors.affiliation: Department of Experimental and Diagnostic Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation (ICSI), Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Marchi
authors.forename: M
authors.initials: M
authors.lastname: Marinello
authors.forename: A
authors.initials: A
authors.lastname: Bononi
authors.forename: M
authors.initials: M
authors.lastname: Bonora
authors.forename: C
authors.initials: C
authors.lastname: Giorgi
authors.forename: A
authors.initials: A
authors.lastname: Rimessi
authors.forename: P
authors.initials: P
authors.lastname: Pinton
mesh_terms: D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D014162:Transfection
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D051057:Proto-Oncogene Proteins c-akt; D002118:Calcium