title: Adrenaline potentiates insulin-stimulated PKB activation via cAMP and Epac: implications for cross talk between insulin and adrenaline.
abstract: Adrenaline and insulin are two of the most important hormones regulating a number of physiological processes in skeletal muscle. Insulin's effects are generally requiring PKB and adrenaline effects cAMP and PKA. Recent evidence indicates cAMP can regulate PKB in some cell types via Epac (Exchange protein directly activated by cAMP). This suggests possible crossover between insulin and adrenaline signalling in muscle. Here we find that adrenaline alone did not influence PKB activation, but adrenaline dramatically potentiated insulin-stimulated phosphorylation of PKB (both Ser473 and Thr308) and of PKBalpha and PKBbeta enzyme activities. These effects were inhibited by wortmannin but adrenaline did not increase insulin-stimulated p85alpha PI 3-kinase activity. Adrenaline effects occurred via beta-adrenergic receptors and accumulation of cAMP. Interestingly, the Epac specific cAMP analogue 8-(4-chlorophenylthio)-2'-O-methyl-cAMP potentiated insulin-stimulated PKB phosphorylation in a similar manner as adrenaline did without activating glycogen phosphorylase. Inhibition of PKA by H89 decreased adrenaline-stimulated glycogen phosphorylase activation but increased PKB activation, which further supports that adrenaline increases insulin-stimulated PKB phosphorylation via Epac. Further, while adrenaline and the Epac activator alone did not promote p70(S6K) Thr389 phosphorylation, they potentiated insulin effects. In conclusion, adrenaline potentiates insulin-stimulated activation of PKB and p70(S6K) via cAMP and Epac in skeletal muscle. Furthermore, the fact that adrenaline alone did not activate PKB or p70(S6K) suggests that a hormone can be a potent regulator of signalling despite no effects being seen when co-activators are lacking.
authors.affiliation: Department of Physiology, National Institute of Occupational Health, P.O. Box 8149 Dep., N-0033, Oslo, Norway.
authors.forename: Erlend O
authors.initials: EO
authors.lastname: Brennesvik
authors.forename: Chariklia
authors.initials: C
authors.lastname: Ktori
authors.forename: Jérôme
authors.initials: J
authors.lastname: Ruzzin
authors.forename: Einar
authors.initials: E
authors.lastname: Jebens
authors.forename: Peter R
authors.initials: PR
authors.lastname: Shepherd
authors.forename: Jørgen
authors.initials: J
authors.lastname: Jensen
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D004357:Drug Synergism; D004837:Epinephrine / Q000378:metabolism*; D024981:Glycogen Phosphorylase / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013912:Threonine / Q000378:metabolism; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D007328:Insulin; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011943:Receptors, Adrenergic, beta; D013912:Threonine; D012694:Serine; D000242:Cyclic AMP; D024981:Glycogen Phosphorylase; D017346:Protein Serine-Threonine Kinases; D000077191:Wortmannin; D004837:Epinephrine