title: Cytoplasmic BK(Ca) channel intron-containing mRNAs contribute to the intrinsic excitability of hippocampal neurons.
abstract: High single-channel conductance K+ channels, which respond jointly to membrane depolarization and micromolar concentrations of intracellular Ca2+ ions, arise from extensive cell-specific alternative splicing of pore-forming alpha-subunit mRNAs. Here, we report the discovery of an endogenous BK(Ca) channel alpha-subunit intron-containing mRNA in the cytoplasm of hippocampal neurons. This partially processed mRNA, which comprises approximately 10% of the total BK(Ca) channel alpha-subunit mRNAs, is distributed in a gradient throughout the somatodendritic space. We selectively reduced endogenous cytoplasmic levels of this intron-containing transcript by RNA interference without altering levels of the mature splice forms of the BK(Ca) channel mRNAs. In doing so, we could demonstrate that changes in a unique BK(Ca) channel alpha-subunit intron-containing splice variant mRNA can greatly impact the distribution of the BK(Ca) channel protein to dendritic spines and intrinsic firing properties of hippocampal neurons. These data suggest a new regulatory mechanism for modulating the membrane properties and ion channel gradients of hippocampal neurons.
authors.affiliation: Department of Pharmacology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Bell
authors.forename: Kevin Y
authors.initials: KY
authors.lastname: Miyashiro
authors.forename: Jai-Yoon
authors.initials: JY
authors.lastname: Sul
authors.forename: Ronald
authors.initials: R
authors.lastname: McCullough
authors.forename: Peter T
authors.initials: PT
authors.lastname: Buckley
authors.forename: Jeanine
authors.initials: J
authors.lastname: Jochems
authors.forename: David F
authors.initials: DF
authors.lastname: Meaney
authors.forename: Phil
authors.initials: P
authors.lastname: Haydon
authors.forename: Charles
authors.initials: C
authors.lastname: Cantor
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Parsons
authors.forename: James
authors.initials: J
authors.lastname: Eberwine
mesh_terms: D000200:Action Potentials; D000818:Animals; D002478:Cells, Cultured; D003712:Dendrites; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D007438:Introns; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics*; D034741:RNA, Small Interfering; D051381:Rats; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: C494842:Kcnma1 protein, rat; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D012333:RNA, Messenger; D034741:RNA, Small Interfering