title: Regulation of proton-coupled folate transporter in retinal Müller cells by the antipsoriatic drug monomethylfumarate.
abstract: Fumaric acid esters are used to treat psoriasis, an inflammatory skin disease characterized by keratinocyte proliferation. Inflammation and proliferation are hallmarks of retinal disease; hence, fumaric acid esters may have therapeutic value in retinal pathology. In diseased retinas, Müller glial cells (MCs) undergo reactive gliosis, a hyperproliferative state. MCs take up folate, a vitamin necessary for cell proliferation, via the proton-coupled folate transporter (PCFT). Here we examined the effect of monomethylfumarate (MMF), the active metabolite of fumaric acid esters, on expression and function of PCFT in MCs. Primary MCs, isolated from neonatal mouse retinas, were treated with MMF, and PCFT function was monitored by measuring uptake of radiolabeled methyltetrahydrofolate (MTF) at pH 5.5. Dose-response and time-course analyses were performed to identify optimal conditions for maximal effect. The influence of MMF treatment on kinetic parameters of PCFT was studied, and PCFT expression was analyzed at the mRNA and protein level. MTF uptake in MCs decreased by ˜50% following 18 h treatment with 1 mM MMF. This effect was specific to fumaric acid esters. MMF treatment decreased the maximal velocity of the transporter without altering substrate affinity. The decrease in PCFT function following MMF treatment was accompanied by attenuated PCFT expression. This is the first report that an antipsoriatic compound can regulate folate transport in MCs and may have potential for the treatment of reactive gliosis in retinal disease.
authors.affiliation: Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Health Sciences University, Augusta, Georgia 30912-2000, USA.
authors.forename: B Renee
authors.initials: BR
authors.lastname: Bozard
authors.forename: Paresh P
authors.initials: PP
authors.lastname: Chothe
authors.forename: Amany
authors.initials: A
authors.lastname: Tawfik
authors.forename: Cory
authors.initials: C
authors.lastname: Williams
authors.forename: Sadanand
authors.initials: S
authors.lastname: Fulzele
authors.forename: Puttur D
authors.initials: PD
authors.lastname: Prasad
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Martin
authors.forename: Vadivel
authors.initials: V
authors.lastname: Ganapathy
authors.forename: Sylvia B
authors.initials: SB
authors.lastname: Smith
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D014150:Antipsychotic Agents; D003879:Dermatologic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D058975:Folate Receptor 1 / Q000235:genetics / Q000378:metabolism; D005650:Fumarates / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D008298:Maleates / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000187:drug effects*; D009525:Niacin / Q000494:pharmacology; D058979:Proton-Coupled Folate Transporter / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000166:cytology*; D013997:Time Factors; D014316:Tritium / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D003879:Dermatologic Agents; D058975:Folate Receptor 1; D005650:Fumarates; C473652:Hcar2 protein, mouse; D008298:Maleates; D058979:Proton-Coupled Folate Transporter; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D014665:Vasodilator Agents; C073341:citraconic acid; D014316:Tritium; D009525:Niacin
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