Beta 2-adrenoreceptors stimulate c-fos transcription through multiple cyclic AMP- and Ca(2+)-responsive elements in cerebellar granular neurons.
Neurons from the granular layer of the cerebellum express functional beta 2-adrenoreceptors (beta 2-ARs). We show that stimulation of beta 2-ARs with isoprenaline increases cyclic AMP (cAMP) production and stimulates transcription of genes containing the cAMP-responsive element (CRE; TGACGTCA). This effect is mediated by cAMP-dependent protein kinase and the trans-acting factor CRE binding protein. Transcriptional regulation by the beta 2-AR was investigated by using the c-fos protooncogene as a model system. We show that beta 2-ARs stimulate c-fos mRNA accumulation, increase AP1 binding activity, and stimulate transcription through the phorbol ester-responsive element (TGACTCA). The transcriptional regulation of c-fos itself was studied with reporter constructs driven by c-fos promoter sequences. Deletion studies revealed that beta 2-ARs stimulate c-fos transcription through at least three distinct regulatory sequences: (a) the CRE located at -60 bp 5' to the initiation site, (b) the fos AP1-like element (-291 to -297), and (c) the serum-responsive element (-297 to -317). The regulation of these elements by the two putative second messengers of the beta 2-AR, cAMP and Ca2+, was analyzed. We report that all three of these regulatory sequences are coregulated by both second messengers. These results indicate that beta 2-ARs stimulate c-fos transcription by multiple cAMP- and Ca(2+)-dependent regulatory elements in neurons.
Barthel
F
F
Institut de Physiologie et de Chimie Biologique, URA 1446 du CNRS, Strasbourg, France.
Loeffler
J P
JP
D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D002531:Cerebellum / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000032:analysis / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000494:pharmacology; D015870:Gene Expression; D016762:Genes, fos / Q000235:genetics*; D007545:Isoproterenol / Q000494:pharmacology; D008969:Molecular Sequence Data; D009474:Neurons / Q000737:chemistry* / Q000166:cytology* / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018343:Receptors, Adrenergic, beta-2 / Q000032:analysis / Q000187:drug effects / Q000502:physiology*; D015290:Second Messenger Systems / Q000502:physiology; D014157:Transcription Factors / Q000032:analysis / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology
D017362:Cyclic AMP Response Element-Binding Protein; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D018343:Receptors, Adrenergic, beta-2; D014157:Transcription Factors; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D007545:Isoproterenol; D002118:Calcium