Regulation of ania‐6 splice variants by distinct signaling pathways in striatal neurons

Abstract The striatum is a brain region involved in motor control and in diverse forms of implicit memory. It is also involved in the pathogenesis of many significant human disorders, including drug addiction, that are thought to involve adaptive changes in gene expression. We have previously shown that the cyclin L, ania‐6, is expressed as at least two splice forms, which are differentially regulated in striatal neurons by different neurotransmitters. Here, we report that ania‐6 transcription is mostly regulated via cAMP response element binding protein (CREB), but that signaling pathways that converge on CREB at the transcriptional level produce different effects on splicing and neuronal gene expression. Glutamate induced a long ania‐6 mRNA that encodes a truncated form of the cyclin. This effect depended on the activation of NMDA receptors but was independent of both calcium/calmodulin‐dependent protein kinases (CaMK) and extracellular regulated kinase (ERK). Forskolin or brain‐derived neurotropic factor (BDNF) induced a short ania‐6 mRNA, that encodes the full‐length cyclin, and this induction depended on ERK. However, KCl‐mediated induction of ania‐6 short mRNA, which required activation of L ‐type calcium channels, was independent of ERK but depended on CaMK. These data suggest that different neuronal signals can differentially regulate splicing and that different intracellular pathways can be recruited to yield a given splice variant.