Isobutylmethylxanthine stimulates adenylate cyclase by blocking the inhibitory regulatory protein, Gi.
The methylxanthines, such as caffeine and theophylline, are an important and widely used class of drugs, which are believed to mediate many of their physiological effects by increasing intracellular concentrations of cAMP. These agents are known to inhibit phosphodiesterases and to block inhibitory A1 adenosine receptors in a competitive manner. Thus, the methylxanthines may increase cAMP accumulation by slowing its inactivation or by enhancing its production. Using a rat adipocyte membrane model we demonstrate that isobutylmethylxanthine (IBMX) induces a dose-dependent 34% increase in cAMP production above that produced by complete phosphodiesterase inhibition with papaverine. This stimulatory effect is dependent upon the inhibitory guanine nucleotide regulatory protein G1, in that inactivation of Gi by pertussis intoxication ablates IBMX-mediated stimulation of adenylate cyclase activity. Because the Gi-dependent effect of IBMX results in increased cAMP production, the mode of action is likely blockade of Gi activity. Accordingly, the capacity of GTP itself to inhibit adenylate cyclase activity is attenuated by IBMX. In contrast to Gi blockade induced by pertussis toxin, this heretofore unappreciated stimulatory mechanism is completely reversed by inhibitory receptor agonists. This mechanism of action may be responsible for certain physiological effects of methylxanthines, which are not easily explained by phosphodiesterase inhibition or antagonism of A1 adenosine receptors.
Parsons
W J
WJ
Department of Medicine (Cardiology), Duke University Medical Center, Durham, North Carolina 27710.
Ramkumar
V
V
Stiles
G L
GL
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology*; D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000032:analysis*; D000818:Animals; D000242:Cyclic AMP / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors*; D006160:Guanosine Triphosphate / Q000494:pharmacology; D008297:Male; D037342:Pertussis Toxin; D051381:Rats; D011919:Rats, Inbred Strains; D013806:Theophylline / Q000031:analogs & derivatives*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D010566:Virulence Factors, Bordetella; D006160:Guanosine Triphosphate; D013806:Theophylline; D000242:Cyclic AMP; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D015056:1-Methyl-3-isobutylxanthine