3,5,3'-Triiodothyronine increases cellular adenosine 3',5'-monophosphate concentration and sugar uptake in rat thymocytes by stimulating adenylate cyclase activity: studies with the adenylate cyclase inhibitor MDL 12330A.
We have previously demonstrated that T3 increases adenylate cyclase activity in preparations of plasma membranes from rat thymocytes. On the basis of this and other evidence, we have postulated that the increased cAMP concentration and consequent increase in 2-deoxyglucose (dGlc) uptake that T3 induces in the intact thymocyte is the consequence of a similar stimulation of adenylate cyclase activity. To obtain further evidence to this point, we have now conducted experiments with MDL 12330A [N-(cis-2-phenyl-cyclopentyl) azacyclotridecan-2-imine-hydrochloride], a compound that inhibits adenylate cyclase activity in several other tissues. In thymocyte plasma membrane preparations, MDL 12330A induced a concentration-dependent inhibition of both basal enzyme activity (activity in the absence of hormone) and the increase in activity induced by T3 and epinephrine. In the intact thymocyte, MDL 12330A greatly limited the marked increase in cellular cAMP concentration induced by maximally effective concentrations of the phosphodiesterase inhibitor 3'-isobutyl-1'-methylxanthine. This indicates that MDL 12330A inhibits adenylate cyclase activity in the intact thymocyte as it does in thymocyte plasma membrane preparations. Further, in intact thymocytes incubated with MDL 12330A, there occurred small but significant decreases in basal cAMP concentration and dGlc uptake, and the T3-induced enhancement of these functions was reduced or abolished. These data provide additional evidence that the increase in dGlc uptake in rat thymocytes that T3 induces is linked to an antecedent increase in cellular cAMP concentration, and that the latter results from a T3-induced enhancement of adenylate cyclase activity.
Segal
J
J
Charles A. Dana Research Institute, Boston, Massachusetts.
Ingbar
S H
SH
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D002147:Calmodulin / Q000494:pharmacology; D050260:Carbohydrate Metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D004837:Epinephrine / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D007097:Imines / Q000494:pharmacology*; D009994:Osmolar Concentration; D051381:Rats; D013950:Thymus Gland / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D014284:Triiodothyronine / Q000494:pharmacology*
D000067956:Adenylyl Cyclase Inhibitors; D002147:Calmodulin; D007097:Imines; D014284:Triiodothyronine; C014925:RMI 12330A; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D005947:Glucose; D015056:1-Methyl-3-isobutylxanthine; D004837:Epinephrine