Regulating ankyrin dynamics: Roles of sigma-1 receptors.
Ankyrin is a cytoskeletal adaptor protein that controls important cellular functions, including Ca(2+) efflux at inositol 1,4,5-trisphosphate receptors (IP(3)R) on the endoplasmic reticulum. The present study found that sigma-1 receptors (Sig-1R), unique endoplasmic reticulum proteins that bind certain steroids, neuroleptics, and psychotropic drugs, form a trimeric complex with ankyrin B and IP(3)R type 3 (IP(3)R-3) in NG-108 cells. The trimeric complex could be coimmunoprecipitated by antibodies against any of the three proteins. Sig-1R agonists such as pregnenolone sulfate and cocaine caused the dissociation of an ankyrin B isoform (ANK 220) from IP(3)R-3. This effect caused by Sig-1R agonists was blocked by a Sig-1R antagonist. The degree of dissociation of ANK 220 from IP(3)R-3 caused by Sig-1R ligands correlates excellently with the ligands' efficacies in potentiating the bradykinin-induced increase in cytosolic free Ca(2+) concentration. Immunocytohistochemistry showed that Sig-1R, ankyrin B, and IP(3)R-3 are colocalized in NG-108 cells in perinuclear areas and in regions of cell-to-cell communication. These results suggest that Sig-1R and associated ligands may play important roles in cells by controlling the function of cytoskeletal proteins and that the Sig-1R/ANK220/IP(3)R-3 complex regulating Ca(2+) signaling may represent a site of action for neurosteroids and cocaine.
Hayashi
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Cellular Pathobiology Unit, Cellular Neurobiology Research Branch, Intramural Research Program, National Institute on Drug Abuse/National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.
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D017487:Ankyrins / Q000378:metabolism*; D015220:Calcium Channels / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology*; D002450:Cell Communication; D003042:Cocaine / Q000494:pharmacology; D005910:Glioma / Q000473:pathology; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D046911:Macromolecular Substances; D018613:Microscopy, Confocal; D009363:Neoplasm Proteins / Q000502:physiology; D009447:Neuroblastoma / Q000473:pathology; D011284:Pregnenolone / Q000494:pharmacology; D020033:Protein Isoforms / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D017480:Receptors, sigma / Q000819:agonists / Q000502:physiology*; D014407:Tumor Cells, Cultured; D000097605:Sigma-1 Receptor
D017487:Ankyrins; D015220:Calcium Channels; D003042:Cocaine; D053496:Inositol 1,4,5-Trisphosphate Receptors; D046911:Macromolecular Substances; D009363:Neoplasm Proteins; D011284:Pregnenolone; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C506926:ITPR1 protein, human; C018370:pregnenolone sulfate