title: Fragile X mental retardation protein regulates protein expression and mRNA translation of the potassium channel Kv4.2.
abstract: A prominent characteristic of the inherited intellectual impairment disease fragile X syndrome (FXS) is neuronal hyperexcitability, resulting in a variety of symptoms, such as hyperactivity, increased sensitivity to sensory stimuli, and a high incidence of epileptic seizures. These symptoms account for a significant part of the disease pattern, but the underlying molecular mechanisms of neuronal hyperexcitability in FXS remain poorly understood. FXS is caused by loss of expression of fragile X mental retardation protein (FMRP), which regulates synaptic protein synthesis and is a key player to limit signaling pathways downstream of metabotropic glutamate receptors 1/5 (mGlu1/5). Recent findings suggest that FMRP might also directly regulate voltage-gated potassium channels. Here, we show that total and plasma membrane protein levels of Kv4.2, the major potassium channel regulating hippocampal neuronal excitability, are reduced in the brain of an FXS mouse model. Antagonizing mGlu5 activity with 2-methyl-6-(phenylethynyl)-pyridine (MPEP) partially rescues reduced surface Kv4.2 levels in Fmr1 knock-out (KO) mice, suggesting that excess mGlu1/5 signal activity contributes to Kv4.2 dysregulation. As an additional mechanism, we show that FMRP is a positive regulator of Kv4.2 mRNA translation and protein expression and associates with Kv4.2 mRNA in vivo and in vitro. Our results suggest that absence of FMRP-mediated positive control of Kv4.2 mRNA translation, protein expression, and plasma membrane levels might contribute to excess neuronal excitability in Fmr1 KO mice, and thus imply a potential mechanism underlying FXS-associated epilepsy.
authors.affiliation: Departments of Cell Biology and Neurology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Gross
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Yao
authors.forename: Dan L
authors.initials: DL
authors.lastname: Pong
authors.forename: Andreas
authors.initials: A
authors.lastname: Jeromin
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Bassell
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D020121:5' Untranslated Regions / Q000235:genetics; D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D019921:Biotinylation; D015153:Blotting, Western; D017931:DNA Primers; D003712:Dendrites / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000502:physiology*; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011132:Polyribosomes / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism; D012640:Seizures / Q000503:physiopathology; D051672:Shal Potassium Channels / Q000096:biosynthesis* / Q000235:genetics*; D013569:Synapses / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D000199:Actins; D017931:DNA Primers; D051860:Fragile X Messenger Ribonucleoprotein 1; D012333:RNA, Messenger; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D051672:Shal Potassium Channels