Methylation-related metabolic effects of D4 dopamine receptor expression and activation

Abstract

D4 dopamine receptor (D4R) activation uniquely promotes methylation of plasma membrane phospholipids, utilizing folate-derived methyl groups provided by methionine synthase (MS). We evaluated the impact of D4R expression on folate-dependent phospholipid methylation (PLM) and MS activity, as well as cellular redox and methylation status, in transfected CHO cells expressing human D4R variants containing 2, 4, or 7 exon III repeats (D4.2R, D4.4R, D4.7R). Dopamine had no effect in non-transfected CHO cells, but increased PLM to a similar extent for both D4.2R- and D4.4R-expressing cells, while the maximal increase was for D4.7R was significantly lower. D4R expression in CHO cells decreased basal MS activity for all receptor subtypes and conferred dopamine-sensitive MS activity, which was greater with a higher number of repeats. Consistent with decreased MS activity, D4R expression decreased basal levels of methylation cycle intermediates methionine, S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH), as well as cysteine and glutathione (GSH). Conversely, dopamine stimulation increased GSH, SAM, and the SAM/SAH ratio, which was associated with a more than 2-fold increase in global DNA methylation. Our findings illustrate a profound influence of D4R expression and activation on MS activity, coupled with the ability of dopamine to modulate cellular redox and methylation status. These previously unrecognized signaling activities of the D4R provide a unique link between neurotransmission and metabolism.

Influences of Folate Supplementation on Homocysteine and Cognition in Patients with Folate Deficiency and Cognitive Impairment

“…MS activity is essential for D4 dopamine-mediated phospholipid methylation (PLM), which was proposed to play a central role in attention and cognition. Thus the improvement associated with folic acid supplementation and lower Hcy levels can be most directly explained by an improvement in MS activity and D4 dopamine receptor-mediated PLM [ 46 ]. Reactive oxygen radicals produced by Hcy is associated with amyloid β protein (Aβ pathology [ 45 , 47 ], thereby potentiating the neurotoxic effects of Aβ on its own or via homocysteic acid.…”

“…The reason why cognitive function significantly improved for a short period after folate supplementation remains unclear. One possibility was mentioned above, folic acid supplementation and lower Hcy levels can improve MS activity and D4 dopamine receptor-mediated PLM, which were proposed to play a central role in attention and cognition [ 46 ]. Another possibility is that folate deficiency is one of the risk factors for depression [ 27 ].…”

Hyperhomocysteinemia: Metabolic Role and Animal Studies with a Focus on Cognitive Performance and Decline—A Review

“…(f) A special kind of methylation cycle arises from the ability of the methionine synthase to catalyze also protein-bound HCys, as in the case of the D4 dopamine receptor (D4). Stimulation of D4-bound methionine leads via D4-bound SAM to methylation of membrane phospholipids [17].…”

Effects of Supplementation with Folic Acid and Its Combinations with Other Nutrients on Cognitive Impairment and Alzheimer’s Disease: A Narrative Review

“…Of interest, it should be underlined that MMSE score improvement was positively correlated with Hcy level at the baseline and its reduction by FA supplementation; however, no significant correlations were found between the degree of MMSE change by folate supplementation and the degree of hippocampal atrophy [ 44 ]. Despite the fact that the mechanisms by which FA supplementation improve cognitive function remain unclear, it has been hypothesized that FA supplementation and lower Hcy levels might improve methionine synthase activity and D4 dopamine receptor-mediated phospholipid methylation, which have been reported to play a key role in attention and cognition [ 51 ].…”