Ca(2+) signaling via sigma(1)-receptors: novel regulatory mechanism affecting intracellular Ca(2+) concentration.
The sigma(1)-receptor is a one-transmembrane endoplasmic reticulum protein that binds neurosteroids and dextrorotatory benzomorphans. The roles of sigma(1)-receptors in regulating intracellular Ca(2+) in NG108 cells were examined in this study. sigma(1)-Ligands pregnenolone sulfate, (+)-pentazocine, and 2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate hydrochloride modulate Ca(2+) signaling in NG108 cells via two modes of action. First, nanomolar concentrations of the ligands, without effect by themselves, potentiated the bradykinin-induced increase of the cytosolic free Ca(2+) concentration in a bell-shaped manner. This effect of sigma(1)-ligands was unaffected by depletion of Ca(2+) from perfusion buffer and was blocked by a 21-mer antisense oligodeoxynucleotide against the cloned sigma(1)-receptors. Second, after the cells were depleted of the endoplasmic reticulum Ca(2+) stores, the depolarization (75 mM KCl)-induced increase in cytosolic free Ca(2+) was potentiated by 2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate hydrochloride, whereas it was inhibited by pregnenolone sulfate and (+)-pentazocine. These effects, albeit opposite in direction, were blocked by both the 21-mer antisense oligodeoxynucleotide and pertussis toxin. Western blotting indicates that sigma(1)-receptors are increased on the plasma membrane and the nuclear membrane in the presence of sigma(1)-ligand. These results suggest that Ca(2+) signaling via sigma(1)-receptors may represent a novel mechanism that affects intracellular Ca(2+) concentrations.
Hayashi
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Cellular Pathobiology Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.
Maurice
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Su
T P
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D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D016291:Dizocilpine Maleate / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010423:Pentazocine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011284:Pregnenolone / Q000494:pharmacology; D011817:Rabbits; D017480:Receptors, sigma / Q000502:physiology*; D014407:Tumor Cells, Cultured
D009025:Morpholines; D016376:Oligonucleotides, Antisense; D017480:Receptors, sigma; C018370:pregnenolone sulfate; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate; D011189:Potassium Chloride; D016291:Dizocilpine Maleate; D011284:Pregnenolone; D009543:Nifedipine; D010423:Pentazocine; D001920:Bradykinin; D002118:Calcium