Molecular pharmacology of glutamate transporters, EAATs and VGLUTs.

As the most predominant excitatory neurotransmitter, glutamate has the potential to influence the function of most neuronal circuits in the central nervous system. To limit receptor activation during signaling and prevent the overstimulation of glutamate receptors that can trigger excitotoxic mechanisms and cell death, extracellular concentrations of excitatory amino acids are tightly controlled by transport systems on both neurons and glial cells. L-Glutamate is a potent neurotoxin, and the inadequate clearance of excitatory amino acids may contribute to the neurodegeneration seen in a variety of conditions, including epilepsy, ischemia, and amyotrophic lateral sclerosis. To establish the contributions of carrier systems to the etiology of neurological disorders, and to consider their potential utility as therapeutic targets, a detailed understanding of transporter function and pharmacology is required. This review summarizes current knowledge of the structural and functional diversity of excitatory amino acid transporters and explores how they might serve as targets for drug design.

Excitatory amino acid transporters: a family in flux.

l-Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system and plays important roles in a wide variety of brain functions, but it is also a key player in the pathogenesis of many neurological disorders. The control of glutamate concentrations is critical to the normal functioning of the central nervous system, and in this review we discuss how glutamate transporters regulate glutamate concentrations to maintain dynamic signaling mechanisms between neurons. In 2004, the crystal structure of a prokaryotic homolog of the mammalian glutamate transporter family of proteins was crystallized and its structure determined. This has paved the way for a better understanding of the structural basis for glutamate transporter function. In this review we provide a broad perspective of this field of research, but focus primarily on the more recent studies with a particular emphasis on how our understanding of the structure of glutamate transporters has generated new insights.

Mechanisms of Glutamate Transport

Excitatory amino acids

The excitatory amino acid transporters: pharmacological insights on substrate and inhibitor specificity of the EAAT subtypes.

Conformationally restricted analogs of naturally-occurring amino acids can serve in a variety of ways as protein structure/function probes. A diastereo- and enantioselective synthesis of the four stereoisomers of 2,3-pyrrolidinedicarboxylic acid (an analog of aspartic acid) are described in this paper. The key step is a Rapoport-type aspartate alkylation that can be controlled to give good yields of either diastereomer as a function of enolate geometry. A novel type of chelation control is proposed to account for these results

Jill A. Hart

Papers

2,3-Pyrrolidinedicarboxylates as Neurotransmitter Conformer Mimics: Enantioselective Synthesis via Chelation-Controlled Enolate Alkylation

L-trans-2,3-Pyrrolidine Dicarboxylate: Characterization of a Novel Excitotoxin

Efficient syntheses of diastereoselectively labeled (3S)-[4-13C]-l-valine, and regioselectively labeled [3-13CH3]-l-isoleucine hydrochlorides