Isoform-specific regulation of adenylyl cyclase by oxidized catecholamines.
Both epinephrine and manganese are known to stimulate cAMP production in cardiac homogenates. When added together, however, they inhibited adenylyl cyclase catalytic activity. Type V adenylyl cyclase, the major isoform in the heart, was also inhibited when an increasing concentration of epinephrine was added in the presence of manganese. Inhibition was not dependent on the condition of stimulation or preparation of the enzyme. However, this inhibition was abolished in the presence of anti-oxidant. Other catecholamines, including dopamine and isoproterenol, as well as adrenochrome, an oxidized product of epinephrine, similarly inhibited the activity of this enzyme. Kinetic analyses revealed that the K(m) for the substrate ATP was unchanged, but the V(max) was significantly decreased. In contrast, type II adenylyl cyclase, a non-cardiac isoform, was resistant to such inhibition by adrenochrome and was somewhat stimulated by it. Thus, catecholamines, when oxidized, directly interacted with adenylyl cyclase in an isoform-specific manner in the absence of G proteins. Our findings suggest that adenylyl cyclase isoforms have different sensitivity to various stresses, including oxidative stress.
Ebina
T
T
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Toya
Y
Y
Oka
N
N
Schwencke
C
C
Kawabe
J
J
Ishikawa
Y
Y
D000262:Adenylyl Cyclases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002395:Catecholamines / Q000378:metabolism* / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008274:Magnesium / Q000378:metabolism / Q000494:pharmacology; D008345:Manganese / Q000378:metabolism / Q000494:pharmacology; D009206:Myocardium / Q000201:enzymology*; D010084:Oxidation-Reduction; D015398:Signal Transduction; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000975:Antioxidants; D002395:Catecholamines; D007527:Isoenzymes; D014662:Vasoconstrictor Agents; D005576:Colforsin; D008345:Manganese; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D008274:Magnesium; D004837:Epinephrine