Inhibition by pregnenolone sulfate of nicotinic acetylcholine response in adrenal chromaffin cells.
To evaluate whether pregnenolone sulfate, an abundant neurosteroid in the brain, modulates nicotinic receptor-mediated responses, the effect of pregnenolone sulfate on acetylcholine-induced catecholamine secretion was investigated in cultured bovine adrenal chromaffin cells. Pregnenolone sulfate inhibited acetylcholine-induced catecholamine secretion (IC(50): 27 microM). In addition, pregnenolone sulfate inhibited acetylcholine-induced Na(+) (IC(50): 12 microM) and Ca(2+) (IC(50): 20 microM) influxes. However, pregnenolone sulfate did not inhibit either catecholamine secretion or Ca(2+) influx stimulated by high K(+). Binding of [3H]nicotine to nicotinic receptors was not altered by pregnenolone sulfate. The inhibitory effect on the acetylcholine-induced secretion was insurmountable by increasing acetylcholine concentrations, but was enhanced by decreasing external Na(+) concentrations. These results suggest strongly that pregnenolone sulfate noncompetitively inhibits nicotinic receptor-operated ion channels, thereby suppressing Na(+) influx through the channels and, consequently, attenuates both Ca(2+) influx and catecholamine secretion. Our results further indicate that pregnenolone sulfate may modulate nicotinic receptor-mediated responses in the brain.
Kudo
Kenzo
K
Department of Pharmacology, School of Medicine, Iwate Medical University, Morioka, Japan. kenzkudo@iwate-med.ac.jp
Tachikawa
Eiichi
E
Kashimoto
Takeshi
T
D000109:Acetylcholine / Q000494:pharmacology*; D000313:Adrenal Medulla / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002395:Catecholamines / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D003164:Competitive Bidding; D004305:Dose-Response Relationship, Drug; D009538:Nicotine / Q000378:metabolism; D011284:Pregnenolone / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism / Q000494:pharmacology; D014316:Tritium
D002395:Catecholamines; D011978:Receptors, Nicotinic; C018370:pregnenolone sulfate; D014316:Tritium; D009538:Nicotine; D011284:Pregnenolone; D012964:Sodium; D000109:Acetylcholine; D002118:Calcium