A study of the cellular mechanism by which lead affects catecholamine secretion.
Our purpose was to determine the role of protein kinases in the mediation of the stimulatory effects of lead on catecholamine secretion. Pheochromocytoma cells were incubated for 90 minutes with W-7 (calmodulin antagonist), calphostin C (protein kinase C inhibitor), Sp-cAMPS (cAMP agonist), Rp-cAMPS (cAMP antagonist), forskolin (activator of adenylyl cyclase), or lead nitrate. Catecholamines were measured by liquid chromatography. Lead had a stimulatory effect on catecholamine secretion, whereas W-7 was inhibitory. In the presence of both lead and W-7, the response was markedly decreased compared to that seen with lead alone. Calphostin C suppressed the secretion of catecholamines; however, in the presence of lead and calphostin C, the secretion was similar to that seen with lead alone. Compared to control, Sp-cAMPS was stimulatory. Co-incubation of Sp-cAMPS and lead had a slight synergistic effect. Rp-cAMPS decreased catecholamine secretion, but co-incubation of Rp-cAMPS and lead resulted in a slight reduction compared to lead alone. Forskolin markedly increased the secretion of catecholamines, and co-incubation of lead and forskolin resulted in a synergistic increase. In the absence of calcium, lead had no effect. We conclude that lead stimulates catecholamine secretion by acting through the calcium/calmodulin-dependent protein kinase II system and not through the protein kinase C or protein kinase A system, and requires the presence of calcium for its action.
Ramin
S M
SM
University of Texas Southwestern Medical Center, Department of Obstetrics & Gynecology, Dallas 75235-9032, USA.
Porter
J C
JC
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002147:Calmodulin / Q000037:antagonists & inhibitors; D002395:Catecholamines / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007854:Lead / Q000494:pharmacology*; D008954:Models, Biological; D009281:Naphthalenes / Q000494:pharmacology; D009566:Nitrates / Q000494:pharmacology; D010673:Pheochromocytoma; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D002147:Calmodulin; D002395:Catecholamines; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D009566:Nitrates; D013449:Sulfonamides; D013873:Thionucleotides; D005576:Colforsin; C016957:adenosine-3',5'-cyclic phosphorothioate; D007854:Lead; C017967:W 7; C017461:lead nitrate; D000242:Cyclic AMP; D011493:Protein Kinase C; D000262:Adenylyl Cyclases; C058819:calphostin C