RNA editing and alternative splicing of human serotonin 2C receptor in schizophrenia

Serotonin 2C receptor (5‐HT2CR) heterogeneity in the brain occurs mostly from two different sources: (i) 5‐HT2CR mRNA undergoes adenosine‐to‐inosine editing events at five positions, which leads to amino acid substitutions that produce receptor variants with different pharmacological properties; (ii) 5‐HT2CR mRNA is alternatively spliced, resulting in a truncated mRNA isoform (5‐HT2CR‐tr) which encodes a non‐functional serotonin receptor. 5‐HT2CR mRNA editing efficiencies and the expression of the full‐length and the truncated 5‐HT2CR mRNA splice isoforms were analyzed in the prefrontal cortex of elderly subjects with schizophrenia vs. matched controls (ns = 15). No significant differences were found, indicating that there are no alterations in editing or alternative splicing of 5‐HT2CRs that are associated with schizophrenia in persons treated with antipsychotic medications. Quantitation of 5‐HT2CR and 5‐HT2CR‐tr mRNA variants revealed that the expression of 5‐HT2CR‐tr was ∼ 50% of that observed for the full‐length isoform.

[1]  Victoria Arango,et al.  Altered Editing of Serotonin 2C Receptor Pre-mRNA in the Prefrontal Cortex of Depressed Suicide Victims , 2002, Neuron.

[2]  K. Nishikura,et al.  A third member of the RNA-specific adenosine deaminase gene family, ADAR3, contains both single- and double-stranded RNA binding domains. , 2000, RNA.

[3]  M. Higuchi,et al.  Cloning of cDNAs encoding mammalian double-stranded RNA-specific adenosine deaminase , 1995, Molecular and cellular biology.

[4]  R. Kahn,et al.  The role of serotonin in schizophrenia. , 1988, Schizophrenia bulletin.

[5]  P. Seeburg,et al.  RNA editing of AMPA receptor subunit GluR-B: A base-paired intron-exon structure determines position and efficiency , 1993, Cell.

[6]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[7]  P. Hartig,et al.  Messenger RNA Editing of the Human Serotonin 5-HT2C Receptor , 1999, Neuropsychopharmacology.

[8]  M Schrey,et al.  Underediting of glutamate receptor GluR-B mRNA in malignant gliomas , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[9]  C. Niswender,et al.  Serotonin 5‐HT2C Receptor RNA Editing Alters Receptor Basal Activity , 1999, Journal of neurochemistry.

[10]  K. Nishikura,et al.  Molecular cloning of cDNA for double-stranded RNA adenosine deaminase, a candidate enzyme for nuclear RNA editing. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Sanjay Tyagi,et al.  Multiplex detection of single-nucleotide variations using molecular beacons. , 1999, Genetic analysis : biomolecular engineering.

[12]  Russell Higuchi,et al.  Kinetic PCR Analysis: Real-time Monitoring of DNA Amplification Reactions , 1993, Bio/Technology.

[13]  R. Glennon,et al.  Agonist activity of LSD and lisuride at cloned 5HT2A and 5HT2C receptors , 1998, Psychopharmacology.

[14]  Andreas Bäbler,et al.  Psilocybin induces schizophrenia‐like psychosis in humans via a serotonin‐2 agonist action , 1998, Neuroreport.

[15]  P. Seeburg,et al.  Structural Requirements for RNA Editing in Glutamate Receptor Pre-mRNAs by Recombinant Double-stranded RNA Adenosine Deaminase (*) , 1996, The Journal of Biological Chemistry.

[16]  W. Keller,et al.  Two forms of human double-stranded RNA-specific editase 1 (hRED1) generated by the insertion of an Alu cassette. , 1997, RNA.

[17]  Sanjay Tyagi,et al.  Molecular Beacons: Probes that Fluoresce upon Hybridization , 1996, Nature Biotechnology.

[18]  K. Davis,et al.  Alzheimer disease and related neurodegenerative diseases in elderly patients with schizophrenia: a postmortem neuropathologic study of 100 cases. , 1998, Archives of general psychiatry.

[19]  K. Davis,et al.  Selective loss of dopamine D3-type receptor mRNA expression in parietal and motor cortices of patients with chronic schizophrenia. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[20]  E. Borrelli,et al.  Preferential coupling between dopamine D2 receptors and G-proteins. , 1993, Molecular endocrinology.

[21]  B. Roth,et al.  5-Hydroxytryptamine2-family receptors (5-hydroxytryptamine2A, 5-hydroxytryptamine2B, 5-hydroxytryptamine2C): where structure meets function. , 1998, Pharmacology & therapeutics.

[22]  M. Martres,et al.  Alternative splicing directs the expression of two D2 dopamine receptor isoforms , 1989, Nature.

[23]  J. Scott,et al.  A place in the world for RNA editing , 1995, Cell.

[24]  P. Seeburg,et al.  A standardized nomenclature for adenosine deaminases that act on RNA. , 1997, RNA.

[25]  D. Goldman,et al.  Identification, expression, and pharmacology of a Cys23-Ser23 substitution in the human 5-HT2c receptor gene (HTR2C). , 1995, Genomics.

[26]  T Kuner,et al.  Control of kinetic properties of AMPA receptor channels by nuclear RNA editing. , 1994, Science.

[27]  R. Emeson,et al.  Regulation of serotonin-2C receptor G-protein coupling by RNA editing , 1997, Nature.

[28]  S. Daviss,et al.  Local circuit neurons of the prefrontal cortex in schizophrenia: selective increase in the density of calbindin-immunoreactive neurons , 1995, Psychiatry Research.

[29]  P S Goldman-Rakic,et al.  Cytoarchitectonic definition of prefrontal areas in the normal human cortex: I. Remapping of areas 9 and 46 using quantitative criteria. , 1995, Cerebral cortex.

[30]  F. Kramer,et al.  Thermodynamic basis of the enhanced specificity of structured DNA probes. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[31]  INTERNATIONAL SOCIETY FOR NEUROCHEMISTRY , 1976 .

[32]  R. Emeson,et al.  Identification, molecular cloning, and distribution of a short variant of the 5-hydroxytryptamine2C receptor produced by alternative splicing. , 1996, Molecular pharmacology.

[33]  K. Nishikura,et al.  Altered G Protein‐Coupling Functions of RNA Editing Isoform and Splicing Variant Serotonin2C Receptors , 2000, Journal of neurochemistry.

[34]  C. Samuel,et al.  Expression and regulation by interferon of a double-stranded-RNA-specific adenosine deaminase from human cells: evidence for two forms of the deaminase , 1995, Molecular and cellular biology.

[35]  M. Martres,et al.  Shorter variants of the D3 dopamine receptor produced through various patterns of alternative splicing. , 1991, Biochemical and biophysical research communications.

[36]  H. Praag,et al.  The role of serotonin in schizophrenia , 1995, European Neuropsychopharmacology.

[37]  Colleen M. Niswender,et al.  RNA Editing of the Human Serotonin 5-Hydroxytryptamine 2C Receptor Silences Constitutive Activity* , 1999, The Journal of Biological Chemistry.

[38]  W H Wong,et al.  Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[39]  Paul J. Harrison,et al.  RNA editing of the 5-HT2C receptor is reduced in schizophrenia , 2001, Molecular Psychiatry.

[40]  P. Seeburg,et al.  A mammalian RNA editing enzyme , 1996, Nature.

[41]  Colleen M Niswender,et al.  RNA Editing of the Human Serotonin 5-HT2C Receptor: Alterations in Suicide and Implications for Serotonergic Pharmacotherapy , 2001, Neuropsychopharmacology.

[42]  K. Nishikura,et al.  Editing of glutamate receptor B subunit ion channel RNAs by four alternatively spliced DRADA2 double-stranded RNA adenosine deaminases , 1997, Molecular and cellular biology.

[43]  V. Haroutunian,et al.  N-methyl-D-aspartic acid receptor expression in the dorsolateral prefrontal cortex of elderly patients with schizophrenia. , 2001, The American journal of psychiatry.

[44]  P. Seeburg,et al.  RNA editing in brain controls a determinant of ion flow in glutamate-gated channels , 1991, Cell.

[45]  Sanjay Tyagi,et al.  Multiplex detection of four pathogenic retroviruses using molecular beacons. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[46]  M. Hanson,et al.  A guide to RNA editing. , 1997, RNA.

[47]  P. Seeburg,et al.  Q/R site editing in kainate receptor GluR5 and GluR6 pre-mRNAs requires distant intronic sequences. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[48]  W. Sadee,et al.  Hydrophobic amino acid in the i2 loop plays a key role in receptor-G protein coupling. , 1993, The Journal of biological chemistry.