The type III inositol 1,4,5-trisphosphate receptor preferentially transmits apoptotic Ca2+ signals into mitochondria.
There are three isoforms of the inositol 1,4,5- trisphosphate receptor (InsP(3)R), each of which has a distinct effect on Ca(2+) signaling. However, it is not known whether each isoform similarly plays a distinct role in the activation of Ca(2+)-mediated events. To investigate this question, we examined the effects of each InsP(3)R isoform on transmission of Ca(2+) signals to mitochondria and induction of apoptosis. Each isoform was selectively silenced using isoform-specific small interfering RNA in Chinese hamster ovary cells, which express all three InsP(3)R isoforms. ATP-induced cytosolic Ca(2+) signaling patterns were altered, regardless of which isoform was silenced, but in a different fashion depending on the isoform. ATP also induced Ca(2+) signals in mitochondria, which were inhibited more effectively by silencing the type III InsP(3)R than by silencing either the type I or type II isoform. The type III isoform also co-localized most strongly with mitochondria. When apoptosis was induced by activation of either the extrinsic or intrinsic apoptotic pathway, induction was reduced most effectively by silencing the type III InsP(3)R. These findings provide evidence that the type III isoform of the InsP(3)R plays a special role in induction of apoptosis by preferentially transmitting Ca(2+) signals into mitochondria.
Mendes
Carolina C P
CC
Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil.
Gomes
Dawidson A
DA
Thompson
Mayerson
M
Souto
Natalia C
NC
Goes
Tercio S
TS
Goes
Alfredo M
AM
Rodrigues
Michele A
MA
Gomez
Marcus V
MV
Nathanson
Michael H
MH
Leite
M Fatima
MF
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D003600:Cytosol / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection
D015220:Calcium Channels; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D000255:Adenosine Triphosphate; D002118:Calcium