A consensus CaMK IV-responsive RNA sequence mediates regulation of alternative exons in neurons.
Neurons make extensive use of alternative pre-mRNA splicing to regulate gene expression and diversify physiological responses. We showed previously in a pituitary cell line that the Ca(++)/calmodulin-dependent protein kinase CaMK IV specifically repressed splicing of the BK channel STREX exon. This repression is dependent on a CaMK IV-responsive RNA element (CaRRE) within the STREX 3' splice site. Here, we report that similar Ca(++) regulation of splicing, mediated by L-type calcium channels and CaM kinase IV, occurs in cultured neurons and in the brain. We identify a critical CaRRE motif (CACATNRTTAT) that is essential for conferring CaMK IV repression on an otherwise constitutive exon. Additional Ca(++)-regulated exons that carry this consensus sequence are also identified in the human genome. Thus, the Ca(++)/CaMK IV pathway in neurons controls the alternative splicing of a group of exons through this short CaRRE consensus sequence. The functions of some of these exons imply that splicing control through the CaMK IV pathway will alter neuronal activity.
Xie
Jiuyong
J
Department of Microbiology, Immunology & Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095-1662, USA.
Jan
Calvin
C
Stoilov
Peter
P
Park
Jennifer
J
Black
Douglas L
DL
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D020746:Calcium Channels, L-Type / Q000502:physiology; D020013:Calcium Signaling; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D016384:Consensus Sequence; D005091:Exons; D017930:Genes, Reporter; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009474:Neurons / Q000502:physiology*; D012313:RNA / Q000737:chemistry / Q000235:genetics*; D012322:RNA Precursors / Q000235:genetics; D051381:Rats; D020218:Response Elements / Q000502:physiology; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid
D020746:Calcium Channels, L-Type; D012322:RNA Precursors; 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