Abstract
Dopaminergic (DA) signaling governs the control of complex behaviors, and its deregulation has been implicated in a wide range of diseases. Here we demonstrate that inactivation of the Fto gene, encoding a nucleic acid demethylase, impairs dopamine receptor type 2 (D2R) and type 3 (D3R) (collectively, 'D2-like receptor')-dependent control of neuronal activity and behavioral responses. Conventional and DA neuron-specific Fto knockout mice show attenuated activation of G protein-coupled inwardly-rectifying potassium (GIRK) channel conductance by cocaine and quinpirole. Impaired D2-like receptor-mediated autoinhibition results in attenuated quinpirole-mediated reduction of locomotion and an enhanced sensitivity to the locomotor- and reward-stimulatory actions of cocaine. Analysis of global N(6)-methyladenosine (m(6)A) modification of mRNAs using methylated RNA immunoprecipitation coupled with next-generation sequencing in the midbrain and striatum of Fto-deficient mice revealed increased adenosine methylation in a subset of mRNAs important for neuronal signaling, including many in the DA signaling pathway. Several proteins encoded by these mRNAs had altered expression levels. Collectively, FTO regulates the demethylation of specific mRNAs in vivo, and this activity relates to the control of DA transmission.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenine / metabolism
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Alpha-Ketoglutarate-Dependent Dioxygenase FTO
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Animals
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Cocaine / pharmacology
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Corpus Striatum / physiology
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Dopamine / physiology*
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Dopaminergic Neurons / enzymology*
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Dopaminergic Neurons / physiology
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Exploratory Behavior / drug effects
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Exploratory Behavior / physiology
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Female
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G Protein-Coupled Inwardly-Rectifying Potassium Channels / physiology
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Locomotion / drug effects
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Locomotion / physiology
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Male
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Mesencephalon / physiology*
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Methylation
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Methyltransferases / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mixed Function Oxygenases / deficiency
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Mixed Function Oxygenases / genetics
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Mixed Function Oxygenases / physiology*
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Oxo-Acid-Lyases / deficiency
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Oxo-Acid-Lyases / genetics
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Oxo-Acid-Lyases / physiology*
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Phenotype
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Quinpirole / pharmacology
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RNA Processing, Post-Transcriptional
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RNA, Messenger / metabolism
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Receptors, Dopamine D2 / deficiency
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Receptors, Dopamine D2 / physiology
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Receptors, Dopamine D3 / physiology
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Reward
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Signal Transduction / drug effects
Substances
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G Protein-Coupled Inwardly-Rectifying Potassium Channels
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RNA, Messenger
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Receptors, Dopamine D2
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Receptors, Dopamine D3
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Quinpirole
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Mixed Function Oxygenases
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FTO protein, mouse
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Alpha-Ketoglutarate-Dependent Dioxygenase FTO
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6-methyladenine mRNA methyltransferase
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Methyltransferases
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Oxo-Acid-Lyases
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Cocaine
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Adenine
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Dopamine