RT Journal Article
SR Electronic
T1 Glutamate-Induced ATP Synthesis: Relationship between Plasma Membrane Na<sup>+</sup>/Ca<sup>2+</sup> Exchanger and Excitatory Amino Acid Transporters in Brain and Heart Cell Models
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 603
OP 614
DO 10.1124/mol.113.087775
VO 84
IS 4
A1 Simona Magi
A1 Sara Arcangeli
A1 Pasqualina Castaldo
A1 Annamaria Assunta Nasti
A1 Liberato Berrino
A1 Elena Piegari
A1 Renato Bernardini
A1 Salvatore Amoroso
A1 Vincenzo Lariccia
YR 2013
UL http://molpharm.aspetjournals.org/content/84/4/603.abstract
AB 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+/Ca2+ 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 Ca2+ 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 Ca2+ 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.