Neurotensin enhances agonist-induced cAMP accumulation in PC3 cells via Ca2+ -dependent adenylyl cyclase(s).
A human prostate cancer cell line (PC3) with abundant neurotensin (NT) receptors was used to demonstrate that NT potentiated 3',5'-cyclic adenosine monophate (cAMP) accumulation in response to a variety of stimuli, including both direct forskolin (F) and indirect (prostaglandin, (PGE2), isoproterenol (ISO) and cholera toxin (CTx)) activators of adenylyl cyclase. Several mechanisms were investigated and our results indicated an effect on the rate of cAMP formation and not on degradation or extrusion. For each stimulus, NT enhanced efficacy without altering EC50. The effect of NT did not involve stimulatory G-protein (Gs)-activation or interference with a tonic inhibitory G-protein (Gi)-mediated inhibition. A similar response was obtained when NT was added with the stimulus or given as a two minute pulse which was removed prior to addition of stimulus. The potentiating activity disappeared with a t1,2 of approximately 15 min. NT transiently elevated cellular [Ca2+]i and its effects on cAMP could be mimicked by [Ca2+]i-elevating agents (uridine triphosphate (UTP), thapsigargin and ionomycin). Buffering cellular [Ca2+]i with 1,2-bis (2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM) inhibited cAMP responses to ISO and F in presence and absence of NT. These data support the idea that NT potentiated cAMP formation in response to a variety of stimuli by facilitating the activation of Ca2+ -dependent adenylyl cyclases.
Carraway
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Department of Physiology, University of Massachusetts Medical Center, Worcester 01655-0127, USA.
Mitra
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D000262:Adenylyl Cyclases / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology; D004357:Drug Synergism; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000819:agonists / Q000502:physiology; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009496:Neurotensin / Q000494:pharmacology*; D011471:Prostatic Neoplasms; D019284:Thapsigargin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014544:Uridine Triphosphate / Q000494:pharmacology
C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D005576:Colforsin; D009496:Neurotensin; D004533:Egtazic Acid; D015759:Ionomycin; D019284:Thapsigargin; D002772:Cholera Toxin; D000242:Cyclic AMP; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019205:GTP-Binding Protein alpha Subunits, Gs; D000262:Adenylyl Cyclases; D015232:Dinoprostone; D007545:Isoproterenol; D002118:Calcium; D014544:Uridine Triphosphate