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Rapid Regulation of Glutamate Transport: Where Do We Go from Here?

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Abstract

Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system (CNS). A family of five Na+-dependent transporters maintain low levels of extracellular glutamate and shape excitatory signaling. Shortly after the research group of the person being honored in this special issue (Dr. Baruch Kanner) cloned one of these transporters, his group and several others showed that their activity can be acutely (within minutes to hours) regulated. Since this time, several different signals and post-translational modifications have been implicated in the regulation of these transporters. In this review, we will provide a brief introduction to the distribution and function of this family of glutamate transporters. This will be followed by a discussion of the signals that rapidly control the activity and/or localization of these transporters, including protein kinase C, ubiquitination, glutamate transporter substrates, nitrosylation, and palmitoylation. We also include the results of our attempts to define the role of palmitoylation in the regulation of GLT-1 in crude synaptosomes. In some cases, the mechanisms have been fairly well-defined, but in others, the mechanisms are not understood. In several cases, contradictory phenomena have been observed by more than one group; we describe these studies with the goal of identifying the opportunities for advancing the field. Abnormal glutamatergic signaling has been implicated in a wide variety of psychiatric and neurologic disorders. Although recent studies have begun to link regulation of glutamate transporters to the pathogenesis of these disorders, it will be difficult to determine how regulation influences signaling or pathophysiology of glutamate without a better understanding of the mechanisms involved.

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Data Availability

Raw data will be made available if requested.

Abbreviations

CNS:

Central nervous system

cAMP:

Cyclic adenosine monophosphate

dbcAMP:

Dibutyryl cyclic adenosine monophosphate

EAAC1:

Excitatory amino acid carrier 1

EAAT:

Excitatory amino acid transporter

GABA:

Gamma aminobutyric acid

GLUT-4:

Glucose transporter type 4

GLAST:

Glutamate aspartate transporter

GLT-1:

Glutamate transporter 1

iGluRs:

Ionotropic glutamate receptors

MDCK:

Madin-Darby Canine Kidney

mGluRs:

Metabotropic glutamate receptors

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MPP+ :

1-Methyl-4-phenylpyridinium

NHERF3:

Na+/H+-exchanger regulatory protein

PPARα:

Peroxisome proliferator-activated receptor-alpha

PDGF:

Platelet-derived growth factor

PDZ:

Post-synaptic density-95/Discs large/Zonula occludens

PKC:

Protein kinase C

WT:

Wild type

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Acknowledgements

The authors would like to thank Dr. Zila Martinez-Lozada for her thoughtful comments and suggestions for improving this review article. The authors were supported by a grant from the National Institutes of Neurologic Disease and Stroke (R01 NS106693).

Funding

The authors were supported by a Grant from the National Institutes of Neurologic Disease and Stroke (R01 NS106693).

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Authors and Affiliations

  1. Department of Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, 19104-4318, USA

    Alain M. Guillem, Elizabeth N. Krizman & Michael B. Robinson

  2. Department of Systems Pharmacology and Translational Therapeutics, Children’s Hospital of Philadelphia, 502N Abramson Pediatric Research Building, 3615 Civic Center Boulevard, Philadelphia, PA, 19104-4318, USA

    Michael B. Robinson

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Contributions

The idea for the topic of this review was developed by AMG and MBR. AMG and MBR gathered literature, and they each drafted parts of the manuscript. AMG, MBR, and ENK all planned the experiments described. AMG and ENK conducted the experiments and performed the data analyses. AMG, MBR, and ENK all contributed to editing and critical revision.

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Correspondence to Michael B. Robinson.

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The work with rats was reviewed and approved by the Children’s Hospital of Philadelphia animal care and use committee and was conducted in accordance with NIH policy.

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Guillem, A.M., Krizman, E.N. & Robinson, M.B. Rapid Regulation of Glutamate Transport: Where Do We Go from Here?. Neurochem Res 47, 61–84 (2022). https://doi.org/10.1007/s11064-021-03329-7

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