title: A conserved serine of heterogeneous nuclear ribonucleoprotein L (hnRNP L) mediates depolarization-regulated alternative splicing of potassium channels.
abstract: Molecular mechanisms of gene regulation underlying the activity-dependent long term changes of cellular electrical properties, such as those during memory, are largely unknown. We have shown that alternative splicing can be dynamically regulated in response to membrane depolarization and Ca(2+)/calmodulin-dependent protein kinase IV (CaMKIV) activation, through special CaM kinase responsive RNA elements. However, proteins that mediate this regulation and how they are affected by CaMKIV are not known. Here we show that the regulation of the stress axis-regulated exon of the Slo1 potassium channel transcripts by membrane depolarization requires a highly conserved CaMKIV target serine (Ser-513) of the heterogeneous ribonucleoprotein L. Ser-513 phosphorylation within the RNA recognition motif 4 enhanced heterogeneous ribonucleoprotein L interaction with the CaMKIV-responsive RNA element 1 of stress axis-regulated exon and inhibited binding of the large subunit of the U2 auxiliary factor U2AF65. Both of these activities were abolished by a S513A mutation. Thus, through Ser-513, membrane depolarization/calcium signaling controls a critical spliceosomal assembly step to regulate the variant subunit composition of potassium channels.
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Manitoba, 745 Bannatyne Ave., Winnipeg, MB R3E 0J9, Canada.
authors.forename: Guodong
authors.initials: G
authors.lastname: Liu
authors.forename: Aleh
authors.initials: A
authors.lastname: Razanau
authors.forename: Yan
authors.initials: Y
authors.lastname: Hai
authors.forename: Jiankun
authors.initials: J
authors.lastname: Yu
authors.forename: Muhammad
authors.initials: M
authors.lastname: Sohail
authors.forename: Vincent G
authors.initials: VG
authors.lastname: Lobo
authors.forename: Jiayou
authors.initials: J
authors.lastname: Chu
authors.forename: Sam K P
authors.initials: SK
authors.lastname: Kung
authors.forename: Jiuyong
authors.initials: J
authors.lastname: Xie
mesh_terms: D017398:Alternative Splicing / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D020013:Calcium Signaling / Q000502:physiology; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000378:metabolism; D002478:Cells, Cultured; D005091:Exons / Q000235:genetics; D034664:Heterogeneous-Nuclear Ribonucleoprotein L / Q000235:genetics / Q000378:metabolism*; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000235:genetics*; D008564:Membrane Potentials / Q000502:physiology*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D010902:Pituitary Gland / Q000166:cytology; D051381:Rats; D012261:Ribonucleoproteins / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D000072668:Splicing Factor U2AF
chemical_list: D034664:Heterogeneous-Nuclear Ribonucleoprotein L; C494842:Kcnma1 protein, rat; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D009687:Nuclear Proteins; D012261:Ribonucleoproteins; D000072668:Splicing Factor U2AF; D012694:Serine; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4