Simultaneous stimulation of GABA and beta adrenergic receptors stabilizes isotypes of activated adenylyl cyclase heterocomplex.
BACKGROUND
We investigated how the synthesis of cAMP, stimulated by isoproterenol acting through beta-adrenoreceptors and Gs, is strongly amplified by simultaneous incubation with baclofen. Baclofen is an agonist of delta-aminobutyric acid type B receptors [GABAB], known to inhibit adenylyl cyclase via Gi. Because these agents have opposite effects on cAMP levels, the unexpected increase in cAMP synthesis when they are applied simultaneously has been intensively investigated. From previous reports, it appears that cyclase type II contributes most significantly to this phenomenon.


RESULTS
We found that simultaneous application of isoproterenol and baclofen specifically influences the association/dissociation of molecules involved in the induction and termination of cyclase activity. Beta/gamma from [GABA]B receptor-coupled Gi has a higher affinity for adenylyl cyclase isoform(s) when these isoforms are co-associated with Gs. Our data also suggest that, when beta/gamma and Galphas are associated with adenylyl cyclase isoform(s), beta/gamma from [GABA]B receptor-coupled Gi retards the GTPase activity of Galphas from adrenergic receptor. These reciprocal regulations of subunits of the adenylyl cyclase complex might be responsible for the drastic increase of cAMP synthesis in response to the simultaneous signals.


CONCLUSIONS
Simultaneous signals arriving at a particular synapse converge on molecular detectors of coincidence and trigger specific biochemical events. We hypothesize that this phenomenon comes from the complex molecular architectures involved, including scaffolding proteins that make reciprocal interactions between associated molecules possible. The biochemistry of simultaneous signaling is addressed as a key to synaptic function.
Robichon
Alain
A
CNRS, University of Burgundy, Centre Européen des Sciences du Goût 15, rue Hugues Picardet DIJON 21000, France. robichon@cesg.cnrs.fr
Tinette
Sylvette
S
Courtial
Cédric
C
Pelletier
Franck
F
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D018755:GABA Agonists / Q000494:pharmacology*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D046912:Multiprotein Complexes; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D018079:Receptors, GABA / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism
D000318:Adrenergic beta-Agonists; C118981:G-protein Beta gamma; D018755:GABA Agonists; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D007527:Isoenzymes; D046912:Multiprotein Complexes; D011943:Receptors, Adrenergic, beta; D018079:Receptors, GABA; D000242:Cyclic AMP; D019205:GTP-Binding Protein alpha Subunits, Gs; D000262:Adenylyl Cyclases; D001418:Baclofen; D007545:Isoproterenol