Post-translational Regulation of GLT-1 in Neurological Diseases and Its Potential as an Effective Therapeutic Target.

Allison R Peterson,Devin K Binder

doi:10.3389/fnmol.2019.00164

Abstract

Glutamate transporter-1 (GLT-1) is a Na+-dependent transporter that plays a key role in glutamate homeostasis by removing excess glutamate in the central nervous system (CNS). GLT-1 dysregulation occurs in various neurological diseases including Huntington’s disease (HD), Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and epilepsy. Downregulation or dysfunction of GLT-1 has been a common finding across these diseases but how this occurs is still under investigation. This review aims to highlight post-translational regulation of GLT-1 which leads to its downregulation including sumoylation, palmitoylation, nitrosylation, ubiquitination, and subcellular localization. Various therapeutic interventions to restore GLT-1, their proposed mechanism of action and functional effects will be examined as potential treatments to attenuate the neurological symptoms associated with loss or downregulation of GLT-1.

Highlights

Glutamate transporter-1 (GLT-1), known as excitatory amino acid transporter 2 (EAAT2), is part of a family of Na+-dependent transporters that regulate extracellular glutamate homeostasis in the central nervous system (CNS)
Glutamate uptake activity is able to recover following a gradual decrease in S-nitrosylation (Raju et al, 2015). It is not known whether GLT-1 S-nitrosylation plays a role in neurological diseases but these findings introduce the opportunity for interventions to increase GLT-1 transporter activity
Glutamate transporter-1 regulation is a critical component in homeostasis of the glutamatergic system

Summary

INTRODUCTION

Glutamate transporter-1 (GLT-1), known as excitatory amino acid transporter 2 (EAAT2), is part of a family of Na+-dependent transporters that regulate extracellular glutamate homeostasis in the CNS. Mice lacking GLT-1 selectively in the dorsal forebrain survive to adulthood and display transient focal seizures (Sugimoto et al, 2018) These findings revealed the important functional role of GLT-1 in extracellular glutamate modulation. Is significantly reduced by approximately 40% whereas deletion of GLT-1 from astrocytes did not show a significant reduction in synaptosomal glutamate uptake capacity (Vmax) These results suggest that neuronal GLT-1 transporters, expressed at low levels, play an important role in glutamate clearance at excitatory synapses where maintaining low levels of extracellular glutamate is critical for proper neuronal function and transmission. Even though GLT-1 is expressed at low levels in axon terminals, studies from the Danbolt and Rosenberg labs showed that neuronal GLT-1 contributes significantly to glutamate uptake in synaptosomes (Danbolt et al, 2016; Rimmele and Rosenberg, 2016; Zhou et al, 2019). Hayden’s group at the TABLE 1 | Glutamate transporter-1 dysregulation in neurological disease models including potential therapeutics to prevent GLT-1 downregulation

Ceftriaxone decreased behavioral deficits and neurodegeneration

Primary astrocyte culture

Subcellular Localization

THERAPEUTIC STRATEGIES

Findings

CONCLUSION