Substrate translocation kinetics of excitatory amino acid carrier 1 probed with laser-pulse photolysis of a new photolabile precursor of D-aspartic acid

Biochemistry. 2001 Jan 9;40(1):232-40. doi: 10.1021/bi0015919.

Abstract

Here we report the synthesis and photochemical and biological characterization of a new photolabile precursor of D-aspartic acid, alpha-carboxynitrobenzyl-caged D-aspartate (alpha-CNB-caged D-aspartate), and its application for studying the molecular mechanism of the neuronal excitatory amino acid carrier 1 (EAAC1). Investigation of the photochemical properties of alpha-CNB-caged D-aspartate by transient absorption spectroscopy of the aci-nitro intermediate revealed that it photolyzes with a quantum yield of 0. 19 at pH 7.0. The major component of the aci-nitro intermediate (77% of the total absorbance) decays with a time constant of 26 s. This decay is slowed by only a factor of 2 when increasing the pH to 10. A minor component (21%) decays with a time constant of 410 s and is pH insensitive. The compound was tested with respect to its biological activity with the glutamate transporter EAAC1 expressed in HEK293 cells. Whole-cell current recordings from these cells in the presence and absence of alpha-CNB-caged D-aspartate demonstrated that the compound neither activates nor inhibits EAAC1. Upon photolysis, D-aspartate-mediated whole-cell currents were generated. In contrast to laser-pulse photolysis experiments with alpha-CNB-caged L-glutamate, only a minor and much slower transient current component was observed. These results indicate that the substrate translocation step, which is not rate-limiting for the overall turnover of the transporter with L-glutamate, becomes rate-limiting when D-aspartate is translocated. The results demonstrate that the new caged D-aspartate derivative is a useful tool for the investigation of the molecular mechanism of glutamate transporters and probably other aspartate translocating systems using rapid chemical kinetic techniques.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System X-AG*
  • Aspartic Acid / analogs & derivatives
  • Aspartic Acid / chemical synthesis
  • Aspartic Acid / metabolism*
  • Aspartic Acid / physiology
  • Biological Transport
  • Carrier Proteins / metabolism*
  • Cell Line
  • Excitatory Amino Acid Transporter 3
  • Glutamate Plasma Membrane Transport Proteins
  • Glutamates / metabolism*
  • Humans
  • Hydrogen-Ion Concentration
  • Kinetics
  • Lasers
  • Models, Biological
  • Models, Chemical
  • Patch-Clamp Techniques
  • Phenylacetates / chemical synthesis
  • Phenylacetates / metabolism*
  • Photolysis*
  • Quantum Theory
  • Symporters*

Substances

  • (carboxy-2-nitrobenzyl)glutamic acid
  • 4-O-(alpha-carboxy-2-nitrobenzyl)aspartic acid
  • Amino Acid Transport System X-AG
  • Carrier Proteins
  • Excitatory Amino Acid Transporter 3
  • Glutamate Plasma Membrane Transport Proteins
  • Glutamates
  • Phenylacetates
  • SLC1A1 protein, human
  • Symporters
  • Aspartic Acid