Cyclic AMP-dependent protein kinase A and CREB are involved in neuregulin-induced synapse-specific expression of acetylcholine receptor gene.
Neuregulin is reported to stimulate synapse-specific transcription of acetylcholine receptor (AChR) genes in the skeletal muscle fiber by multiple signaling pathways such as ERK, PI3K, and JNK. The co-localization of PKA mRNA with AChR and ErbBs, receptors for neuregulin, at the confined region of synapse implicates the putative role of PKA in neuregulin-induced AChR gene expression. In the present study, we found that mRNA and protein of a regulatory subunit of PKA (PKARIalpha) were concentrated at synaptic sites of the rat sternomastoid muscle fiber, while those of ERK and PI3K were uniformly distributed throughout the muscle fiber. Neuregulin (100 ng/ml) increased both PKA activity in the nucleus and AChRdelta subunit gene transcription in cultured Sol8 myotubes. These increases were significantly blocked by a specific PKA inhibitor H-89 (100 nM) and an adenylcyclase inhibitor SQ 22536 (200 microM) (72.5% and 60.1%, respectively). Furthermore, neuregulin phosphorylated CREB, a well-known down-stream transcription factor of PKA. While H-89 inhibited CREB phosphorylation, H-89 and PD098059 (50 microM), a specific MEK1/2 inhibitor, did not inhibit the phosphorylation of ERK and CREB, respectively, suggesting no cross-talk between PKA and ERK pathways. In conclusion, neuregulin increases AChRdelta subunit gene transcription, in part, by the activation of PKA/CREB, an alternative route to the previously reported ERK signaling pathway.
Department of Biomedical Sciences, National Institute of Health, 5 Nokbun-dong, Eunpyung-gu, Seoul 122-701, South Korea.
Byung-Hak
BH
Kang
Inho
I
Jo
Su-Yong
SY
Eun
Sangmee Ahn
SA
Jo
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D005419:Flavonoids / Q000378:metabolism; D005786:Gene Expression Regulation; D007546:Isoquinolines / Q000378:metabolism; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology; D020880:Neuregulins / Q000378:metabolism*; D010766:Phosphorylation; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011950:Receptors, Cholinergic / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides; D013569:Synapses / Q000502:physiology*
D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007546:Isoquinolines; D020880:Neuregulins; D021122:Protein Subunits; D011950:Receptors, Cholinergic; D011993:Recombinant Fusion Proteins; D013449:Sulfonamides; D015124:8-Bromo Cyclic Adenosine Monophosphate; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one