Regulation of GH3-cell function via adenosine A1 receptors. Inhibition of prolactin release, cyclic AMP production and inositol phosphate generation.
We examined the mechanism by which adenosine inhibits prolactin secretion from GH3 cells, a rat pituitary tumour line. Prolactin release is enhanced by vasoactive intestinal peptide (VIP), which increases cyclic AMP, and by thyrotropin-releasing hormone (TRH), which increases inositol phosphates (IPx). Analogues of adenosine decreased prolactin release, VIP-stimulated cyclic AMP accumulation and TRH-stimulated inositol phospholipid hydrolysis and IPx generation. Inhibition of InsP3 production by R-N6-phenylisopropyladenosine (R-PIA) was rapid (15 s) and was not affected by the addition of forskolin or the removal of external Ca2+. Addition of adenosine deaminase or the potent adenosine-receptor antagonist, BW-A1433U, enhanced the accumulation of cyclic AMP by VIP, indicating that endogenously produced adenosine tonically inhibits adenylate cyclase. The potency order of adenosine analogues for inhibition of cyclic AMP and IPx responses (measured in the presence of adenosine deaminase) was N6-cyclopentyladenosine greater than R-PIA greater than 5'-N-ethylcarboxamidoadenosine. This rank order indicates that inhibitions of both cyclic AMP and InsP3 production are mediated by adenosine A1 receptors. Responses to R-PIA were blocked by BW-A1433U (1 microM) or by pretreatment of cells with pertussis toxin. A greater amount of toxin was required to eliminate the effect of R-PIA on inositol phosphate than on cyclic AMP accumulation. These data indicate that adenosine, in addition to inhibiting cyclic AMP accumulation, decreases IPx production in GH3 cells, possibly by directly inhibiting phosphoinositide hydrolysis.
Delahunty
T M
TM
Department of Neuroscience, University of Virginia School of Medicine, Charlottesville 22908.
Cronin
M J
MJ
Linden
J
J
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000243:Adenosine Deaminase / Q000494:pharmacology; D037361:Adenylate Cyclase Toxin; D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D007295:Inositol Phosphates / Q000378:metabolism*; D037342:Pertussis Toxin; D010660:Phenylisopropyladenosine / Q000494:pharmacology; D011388:Prolactin / Q000378:metabolism*; D051381:Rats; D011983:Receptors, Purinergic / Q000378:metabolism*; D013403:Sugar Phosphates / Q000378:metabolism*; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D007295:Inositol Phosphates; D011983:Receptors, Purinergic; D013403:Sugar Phosphates; D010566:Virulence Factors, Bordetella; D014970:Xanthines; D010660:Phenylisopropyladenosine; D013973:Thyrotropin-Releasing Hormone; D011388:Prolactin; C053414:BW A1433U; D000242:Cyclic AMP; D037342:Pertussis Toxin; D000243:Adenosine Deaminase; D000241:Adenosine