Modulation of Ca(2+) release and Ca(2+) oscillations in HeLa cells and fibroblasts by mitochondrial Ca(2+) uniporter stimulation.
The recent availability of activators of the mitochondrial Ca(2+) uniporter allows direct testing of the influence of mitochondrial Ca(2+) uptake on the overall Ca(2+) homeostasis of the cell. We show here that activation of mitochondrial Ca(2+) uptake by 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) or kaempferol stimulates histamine-induced Ca(2+) release from the endoplasmic reticulum (ER) and that this effect is enhanced if the mitochondrial Na(+)-Ca(2+) exchanger is simultaneously inhibited with CGP37157. This suggests that both Ca(2+) uptake and release from mitochondria control the ability of local Ca(2+) microdomains to produce feedback inhibition of inositol 1,4,5-trisphosphate receptors (InsP(3)Rs). In addition, the ability of mitochondria to control Ca(2+) release from the ER allows them to modulate cytosolic Ca(2+) oscillations. In histamine stimulated HeLa cells and human fibroblasts, both PPT and kaempferol initially stimulated and later inhibited oscillations, although kaempferol usually induced a more prolonged period of stimulation. Both compounds were also able to induce the generation of Ca(2+) oscillations in previously silent fibroblasts. Our data suggest that cytosolic Ca(2+) oscillations are exquisitely sensitive to the rates of mitochondrial Ca(2+) uptake and release, which precisely control the size of the local Ca(2+) microdomains around InsP(3)Rs and thus the ability to produce feedback activation or inhibition of Ca(2+) release.
Vay
Laura
L
Instituto de Biología y Genética Molecular (IBGM), Departamento de Bioquímica y Biología Molecular y Fisiología, Facultad de Medicina, Ramón y Cajal, 7, E-47005 Valladolid, Spain.
Hernández-Sanmiguel
Esther
E
Santo-Domingo
Jaime
J
Lobatón
Carmen D
CD
Moreno
Alfredo
A
Montero
Mayte
M
Alvarez
Javier
J
D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002998:Clonazepam / Q000031:analogs & derivatives / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004965:Estrogen Antagonists / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology*; D006367:HeLa Cells; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000187:drug effects; D044949:Kaempferols / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D013268:Stimulation, Chemical; D013841:Thiazepines / Q000494:pharmacology
D015220:Calcium Channels; D004965:Estrogen Antagonists; D053496:Inositol 1,4,5-Trisphosphate Receptors; D044949:Kaempferols; D013841:Thiazepines; C034703:mitochondrial calcium uniporter; D002998:Clonazepam; C006552:kaempferol; C079032:CGP 37157; D006632:Histamine; D002118:Calcium