A CaMK IV responsive RNA element mediates depolarization-induced alternative splicing of ion channels.
Calcium regulation of gene expression is critical for the long-lasting activity-dependent changes in cellular electrical properties that underlie important physiological functions such as learning and memory. Cellular electrical properties are diversified through the extensive alternative splicing of ion channel pre-messenger RNAs; however, the regulation of splicing by cell signalling pathways has not been well explored. Here we show that depolarization of GH3 pituitary cells represses splicing of the STREX exon in BK potassium channel transcripts through the action of Ca2+/calmodulin-dependent protein kinases (CaMKs). Overexpressing constitutively active CaMK IV, but not CaMK I or II, specifically decreases STREX inclusion in the mRNA. This decrease is prevented by mutations in particular RNA repressor sequences. Transferring 54 nucleotides from the 3' splice site upstream of STREX to a heterologous gene is sufficient to confer CaMK IV repression on an otherwise constitutive exon. These experiments define a CaMK IV-responsive RNA element (CaRRE), which mediates the alternative splicing of ion channel pre-mRNAs. The CaRRE presents a unique molecular target for inducing long-term adaptive changes in cellular electrical properties. It also provides a model system for dissecting the effect of signal transduction pathways on alternative splicing.
Xie
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J
Howard Hughes Medical Institute, and Department of Microbiology & Molecular Genetics, University of California Los Angeles, California 90095-1662, USA.
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D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D020013:Calcium Signaling; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D003001:Cloning, Molecular; D005091:Exons; D006801:Humans; D007438:Introns; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008564:Membrane Potentials; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D015221:Potassium Channels / Q000235:genetics*; D024681:Potassium Channels, Calcium-Activated; D012313:RNA / Q000235:genetics*; D012322:RNA Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012045:Regulatory Sequences, Nucleic Acid; D017384:Sequence Deletion; D015398:Signal Transduction
D051036:Large-Conductance Calcium-Activated Potassium Channels; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D012322:RNA Precursors; D012333:RNA, Messenger; D012313:RNA; C517683:CAMK4 protein, human; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517685:Camk4 protein, mouse; C517686:Camk4 protein, rat