title: Methionine Exposure Alters Glutamate Uptake and Adenine Nucleotide Hydrolysis in the Zebrafish Brain.
abstract: Hypermethioninemic patients may exhibit different neurological dysfunctions, and the mechanisms underlying these pathologies remain obscure. Glutamate and ATP are important excitatory neurotransmitters co-released at synaptic clefts, and whose activities are intrinsically related. Adenosine-the final product of ATP breakdown-is also an important neuromodulator. Here, we investigated the effects of long-term (7-day) exposure to 1.5 or 3 mM methionine (Met) on glutamate uptake in brain tissues (telencephalon, optic tectum, and cerebellum) and on ATP, ADP, and AMP catabolism by ecto-nucleotidases found in brain membrane samples, using a zebrafish model. Also, we evaluated the expression of ecto-nucleotidase (ntdp1, ntdp2mg, ntdp2mq, ntdp2mv, ntdp3, and nt5e) and adenosine receptor (adora1, adora2aa, adora2ab, adora2b) genes in the brain of zebrafish exposed to Met. In animals exposed to 3.0 mM Met, glutamate uptake in the telencephalon decreased significantly. Also, ATP and ADP (but not AMP) catabolism decreased significantly at both Met concentrations tested. The messenger RNA (mRNA) levels of ntpd genes and of the adenosine receptors adora1 and adora2aa increased significantly after Met exposure. In contrast, adora2ab mRNA levels decreased after Met exposure. Our data suggest that glutamate and ATP accumulate at synaptic clefts after Met exposure, with potential detrimental effects to the nervous system. This phenomenon might explain, at least in part, the increased susceptibility of hypermethioninemic patients to neurological symptoms.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul., Rua Ramiro Barcelos 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil. fcvuaden@gmail.com.
authors.forename: Fernanda Cenci
authors.initials: FC
authors.lastname: Vuaden
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul., Rua Ramiro Barcelos 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: Luiz Eduardo Baggio
authors.initials: LEB
authors.lastname: Savio
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul., Rua Ramiro Barcelos 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: Eduardo Pacheco
authors.initials: EP
authors.lastname: Rico
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul., Rua Ramiro Barcelos 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: Ben Hur Marins
authors.initials: BHM
authors.lastname: Mussulini
authors.affiliation: Departamento de Bioquímica e Biologia Molecular, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Avenida Roraima, 1000, Santa Maria, RS, 97105-900, Brazil.
authors.forename: Denis Broock
authors.initials: DB
authors.lastname: Rosemberg
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul., Rua Ramiro Barcelos 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: Diogo Losch
authors.initials: DL
authors.lastname: de Oliveira
authors.affiliation: Departamento de Biologia Celular e Molecular, Faculdade de Biociências, Pontifícia Universidade Católica do Rio Grande do Sul, Avenida Ipiranga, 6681, Porto Alegre, RS, 90619-900, Brazil.
authors.forename: Maurício Reis
authors.initials: MR
authors.lastname: Bogo
authors.affiliation: Departamento de Biologia Celular e Molecular, Faculdade de Biociências, Pontifícia Universidade Católica do Rio Grande do Sul, Avenida Ipiranga, 6681, Porto Alegre, RS, 90619-900, Brazil.|Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), Porto Alegre, RS, 90035-003, Brazil.
authors.forename: Carla Denise
authors.initials: CD
authors.lastname: Bonan
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul., Rua Ramiro Barcelos 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil. wyse@ufrgs.br.
authors.forename: Angela T S
authors.initials: ATS
authors.lastname: Wyse
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000592:Amino Acid Metabolism, Inborn Errors / Q000188:drug therapy; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D050938:Glycine N-Methyltransferase / Q000172:deficiency; D006868:Hydrolysis / Q000187:drug effects; D008715:Methionine / Q000494:pharmacology*; D015027:Zebrafish
chemical_list: D018698:Glutamic Acid; D000255:Adenosine Triphosphate; D008715:Methionine; D050938:Glycine N-Methyltransferase; D000251:Adenosine Triphosphatases; C027201:ectoATPase; D000241:Adenosine
keywords: Glutamate uptake; Hypermethioninemia; Inherited diseases; Methionine; Nucleotide catabolism; Zebrafish