Energy Landscape of the Substrate Translocation Equilibrium of Plasma-Membrane Glutamate Transporters.
J Phys Chem B
; 122(1): 28-39, 2018 01 11.
Article
en En
| MEDLINE
| ID: mdl-29218993
ABSTRACT
Glutamate transporters maintain a large glutamate concentration gradient across synaptic membranes and are, thus, critical for functioning of the excitatory synapse. Mammalian glutamate transporters concentrate glutamate inside cells through energetic coupling of glutamate flux to the transmembrane concentration gradient of Na+. Structural models based on an archeal homologue, GltPh, suggest an elevator-like carrier mechanism. However, the energetic determinants of this carrier-based movement are not well understood. Although electrostatics play an important role in governing these energetics, their implication on transport dynamics has not been studied. Here, we combine a pre-steady-state kinetic analysis of the translocation equilibrium with electrostatic computations to gain insight into the energetics of the translocation process. Our results show the biphasic nature of translocation, consistent with the existence of an intermediate on the translocation pathway. In the absence of voltage, the equilibrium is shifted to the outward-facing configuration. Electrostatic computations confirm the intermediate state and show that the elevator-like movement is energetically feasible in the presence of bound Na+ ions, whereas a substrate-hopping model is energetically prohibitive. Our results highlight the critical contribution of charge compensation to transport and add to results from previous molecular dynamics simulations for improved understanding of the glutamate translocation process.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Transportador 3 de Aminoácidos Excitadores
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Phys Chem B
Asunto de la revista:
QUIMICA
Año:
2018
Tipo del documento:
Article
País de afiliación:
Estados Unidos