D4 dopamine receptor-mediated phospholipid methylation and its implications for mental illnesses such as schizophrenia

Abstract

Keywords: receptors; G protein-coupled; phospholipid methylation; methionine; folic acid; membrane fluidity; purines; de novo synthesis Schizophrenia is a complex psychiatric disorder affecting approximately 1% of the population worldwide with a typical onset between the late teens and midthirties, often in the absence of significant prodromal psychiatric symptoms.1 Decades of research have yielded many theories on the origin of schizophrenia, although none provides a satisfying mechanistic explanation. Logically, dysfunctional neurotransmission is the most widely held theory, and specific abnormalities involving dopaminergic, 2 glutamatergic, 3 GABAergic 4 and nicotinic cholinergic 5 signaling have been proposed. Of these, the 'Dopamine Hypothesis' is dominant, based largely on the recognized therapeutic efficacy of drugs which block D2-like dopamine receptors (ie D2, D3 and D4 receptors), although their specific mechanism of benefit and the importance of individual receptor subtypes remains unclear. The D4

Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal

“…31 The discovery of the PI3-kinase/MAP-kinase/MS pathway, and its potent inhibition by developmental neurotoxins, including vaccine components thimerosal and aluminum, provides a potential molecular explanation for how increased use of vaccines could promote an increase in the incidence of autism. The increased incidence of ADHD, which preceded the more recent rise in autism, could represent an alternative manifestation of vaccine-associated neurodevelopmental toxicity, since the D4 dopamine receptor is linked to ADHD 18 and its PLM function depends on MS. 15 There are important limitations to our findings. We utilized a transformed cell line, and molecular events in tumor-derived cells might not mirror those in normal cells.…”

“…[15][16][17] Dopamine activation of the D4 receptor initiates a four-step cycle of phospholipid methylation (PLM) in which the side chain of a methionine residue in the receptor is adenosylated, enabling transfer of its methyl group to the head group of an adjacent phospholipid. Following the removal of the adenosyl group by SAH hydrolase, MS provides a new, folate-derived methyl group to the side chain, thereby supporting dopamine-stimulated PLM.…”

Glyphosate Use Predicts Healthcare Utilization for ADHD in the Healthcare Cost and Utilization Project net (HCUPnet): A Two-Way Fixed-Effects Analysis

“…Methionine synthase inactivity interferes with methylation of the homocysteine subunit of the dopamine receptor 4 [81], leading to an inactivation of dopamineinduced phospholipid methylation (PLM) through dopamine receptor 4 (DR4). NE has been shown to activate DR4 in rat lateral habenula [82], so it is plausible for there to be excess NE amid DR4 inactivation.…”

Dopamine D4 receptors: significance for molecular psychiatry at the millennium

“…59 (2) blocking the Ltype calcium current in cultured granule cells from neonatal rat cerebellum; 63 (3) inhibiting potassium currents in nerve terminals of the neurohypophysis; 64 and (4) facilitating membrane phospholipid methylation in cultured neuroblastoma cell lines. 7 In contrast to their ability to reduce cAMP production in mammotrophic cell lines derived from pituitary lactotrophs, stimulation of the three main human D 4 receptor variants in transfected mammotrophs neither altered the activity of the prolactin promoter region necessary for regulation of prolactin gene transcription nor increased prolactin secretion. 65 Studies of genetically altered, D [70][71][72] Olanzapine, a recently introduced structural analog of clozapine, shares with clozapine some D 4 -over-D 2 selectivity.…”

“…6 Finally, a methionine residue located in TM VI and adjacent to phospholipid headgroup may be involved in facilitating the methylation of membrane phospholipids. 7 The rat D 4 gene was cloned after the initial work with the human DRD4 gene, 8 and found to encode a slightly shorter protein of 368 amino acids (19 fewer) than the human D 4 receptor, and without a 48-amino acid repeat sequence found in the human IL 3 region. The rat D 4 receptor also has one fewer exons (n = 4) and introns (n = 3) than the human D4DR.…”