title: Glutamate-induced ATP synthesis: relationship between plasma membrane Na+/Ca2+ exchanger and excitatory amino acid transporters in brain and heart cell models.
abstract: It is known that glutamate (Glu), the major excitatory amino acid in the central nervous system, can be an essential source for cell energy metabolism. Here we investigated the role of the plasma membrane Na(+)/Ca(2+) exchanger (NCX) and the excitatory amino acid transporters (EAATs) in Glu uptake and recycling mechanisms leading to ATP synthesis. We used different cell lines, such as SH-SY5Y neuroblastoma, C6 glioma and H9c2 as neuronal, glial, and cardiac models, respectively. We first observed that Glu increased ATP production in SH-SY5Y and C6 cells. Pharmacological inhibition of either EAAT or NCX counteracted the Glu-induced ATP synthesis. Furthermore, Glu induced a plasma membrane depolarization and an intracellular Ca(2+) increase, and both responses were again abolished by EAAT and NCX blockers. In line with the hypothesis of a mutual interplay between the activities of EAAT and NCX, coimmunoprecipitation studies showed a physical interaction between them. We expanded our studies on EAAT/NCX interplay in the H9c2 cells. H9c2 expresses EAATs but lacks endogenous NCX1 expression. Glu failed to elicit any significant response in terms of ATP synthesis, cell depolarization, and Ca(2+) increase unless a functional NCX1 was introduced in H9c2 cells by stable transfection. Moreover, these responses were counteracted by EAAT and NCX blockers, as observed in SH-SY5Y and C6 cells. Collectively, these data suggest that plasma membrane EAAT and NCX are both involved in Glu-induced ATP synthesis, with NCX playing a pivotal role.
authors.affiliation: Department of Biomedical Sciences and Public Health, School of Medicine, University Politecnica of Marche, Ancona, Italy (S.M., S.Ar., P.C., A.A.N., S.Am., V.L.); Department of Experimental Medicine, Second University of Naples, Naples, Italy (L.B., E.P.); and Department of Clinical and Molecular Biomedicine, School of Medicine, University of Catania, Catania, Italy (R.B.).
authors.forename: Simona
authors.initials: S
authors.lastname: Magi
authors.forename: Sara
authors.initials: S
authors.lastname: Arcangeli
authors.forename: Pasqualina
authors.initials: P
authors.lastname: Castaldo
authors.forename: Annamaria Assunta
authors.initials: AA
authors.lastname: Nasti
authors.forename: Liberato
authors.initials: L
authors.lastname: Berrino
authors.forename: Elena
authors.initials: E
authors.lastname: Piegari
authors.forename: Renato
authors.initials: R
authors.lastname: Bernardini
authors.forename: Salvatore
authors.initials: S
authors.lastname: Amoroso
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Lariccia
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism*; D018698:Glutamic Acid / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051381:Rats; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*
chemical_list: D027341:Excitatory Amino Acid Transporter 1; C493394:SLC1A3 protein, human; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; D018698:Glutamic Acid; D000255:Adenosine Triphosphate