Abstract
Neuronal activity results in long term cellular changes that underlie normal brain development and synaptic plasticity. To examine the molecular basis of activity-dependent plasticity, we have used differential cloning techniques to identify genes that are rapidly induced in brain neurons by synaptic activity. Here we describe an inducible novel member of the Ras family of small GTP-binding proteins we have termed Rheb. rheb mRNA is rapidly and transiently induced in hippocampal granule cells by seizures and by NMDA-dependent synaptic activity in the long term potentiation paradigm. The predicted amino acid sequence of Rheb is most closely homologous to yeast Ras1 and human Rap2. The putative GTP binding regions are highly conserved. A bacterial fusion protein of Rheb binds GTP and exhibits intrinsic GTPase activity. Like Ha-Ras, the carboxylterminal sequence encodes a CAAX box that is predicted to signal post-translational farnesylation and to target Rheb to specific membranes. rheb mRNA is expressed at comparatively high levels in normal adult cortex as well as a number of peripheral tissues, including lung and intestine. In the developing brain, rheb mRNA is expressed at relatively high levels in embryonic day 19 cortical plate, and expression remains at stable levels throughout the remainder of prenatal and postnatal development. Its close homology with ras and its rapid inducibility by receptor-dependent synaptic activity suggest that rheb may play an important role in long term activity-dependent neuronal responses.
Highlights
Neuronaalctivitryesults in lontgermcellular such as transmitters and growth factors induce the coordinate changes that underlie normal brain development and activation of regulatory genes, which may mediate longterm synaptic plasticity
Rheb mRNA is ex- induction in brain neurons by NMDA-dependent synaptic acpressed at relatively high levels in embryonic day 19 tivity are unique features that suggest a novelrole in long cortical plate, and expression remains at stable levels term, activity-dependent neuronal responses
Construction of Subtracted cDNA Library-Total RNAs wereisolated from hippocampusof naive control adult Sprague-Dawleyrats and from rats treated with cycloheximide (20 mgkg intraperitoneally) 4 h after maximal electroconvulsive seizures (MECS) [11]
Summary
Nucleotide Sequenceof rheb cDNA-Anearly full-length rheb cDNA was obtained from the unsubtracted 4-h MECS hippocampus library. - mRNA was estimated to be -1.4 kilobases, and the size of the cDNA used for sequencing was 1.1kilobases. The sequence has a single long open reading frame of 552 nucleotides that begins 124 nucleotides from the 5' end of the cDNA. The putative 5' noncoding sequence includes an in-frame stop codon 36 nucleotides 5' to the putative translation start site. The open readingframe is followedby an in-frame termination codon and 403 nucleotides of nontranslated 3' sequence. Rheb Protein-Fig. 2 shows the amino acid sequence of the protein encoded in thelong open reading frame of rheb cDNA. Rheb is 184 amino acids long and is 37.7, 43.3, and 34% idenrRheb hRap hH-Ras yH-RAS1 ras-reIlnadteudcibleNovel
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