A CaMK IV responsive RNA element mediates depolarization-induced alternative splicing of ion channels

Calcium regulation of gene expression is critical for the longlasting activ ity-dependent changes in cellular electrical properties that underlie impor tant physiological functions such as learning and memory(1). Cellular elect rical properties are diversified through the extensive alternative splicing of ion channel premessenger RNAs2; however, the regulation of splicing by cell signalling pathways has not been well explored. Here we show that depo larization of GH(3) pituitary cells represses splicing of the STREX exon(3) in BK potassium channel transcripts through the action of Ca2+/calmodulin- dependent protein kinases (CaMKs). Overexpressing constitutively active CaM K IV, but not CaMK I or II, specifically decreases STREX inclusion in the m RNA. This decrease is prevented by mutations in particular RNA repressor se quences. Transferring 54 nucleotides from the 3' splice site upstream of ST REX 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 channe l 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.