Regulating ankyrin dynamics: Roles of sigma-1 receptors

Ankyrin is a cytoskeletal adaptor protein that controls important cellular functions, including Ca2+ efflux at inositol 1,4,5-trisphosphate receptors (IP3R) 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 IP2R type 3 (IP3R-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 IP3R-3, This effect caused by Sig-1R agonists was blocked by a Sig-1R antagonist. The degree of dissociation of ANK 220 from IP3R-3 caused by Sig-1R ligands correlates excellently with the ligands' efficacies in potentiating the bradykinin-induced increase in cytosolic free Ca2+ concentration. Immunocytohistochemistry showed that Sig-1R, ankyrin B, and IP3R-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/IP3R-3 complex regulating Ca2+ signaling may represent a site of action for neurosteroids and cocaine.