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Regulation of the GAT-1 transporter in neuronal cells: action of the Brain-Derived Neurotrophic Fact

By etavares On 30 April, 2011 Science Space | 2011 Comments Off on Regulation of the GAT-1 transporter in neuronal cells: action of the Brain-Derived Neurotrophic Fact No tags

The gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system. The correct finalization and modulation of GABAergic synaptic transmission occurs thanks to the rapid reuptake of GABA in the synaptic cleft by high-affinity GABA transporters located both in neurons’ presynaptic terminal and in the glial cells, namely astrocytes (1).

Until now, four GABA transporters have been identified: GAT-1, GAT-2, GAT-3, and the betaine transporter. The GAT-1 transporter is the predominant GABA transporter in the central nervous system and is preferably expressed in the neurons, although it is equally expressed in the astrocytes (1). It is important to pinpoint that patients with temporal lobe epilepsy present increased expression of GABA transporters in the astrocytes (2), and that GABA transporter inhibitors, or inhibitors of the metabolism of this neurotransmitter, are effective anti-epileptic drugs (3), which attests the relevant role of these transporters in excitability control.

GABA transporters can be regulated in different ways, and several factors and signal transduction cascades are involved in this regulation process. This modulation can occur in two distinct manners: by Km or by Vmax alteration of the transporter. Accordingly, the regulation of continuous trafficking of GABA transporters from and into the neuronal plasma membrane may occur due to variations in endocytosis and exocytosis speed and/or due to change in the amount of available transporters in this trafficking process (4). For example, the expression of the GAT-1 transporter in the neuron cell membrane diminishes when there is PKC activation both in neuronal primary cultures (5) and in neuronal presynaptic terminals (6).

Another molecule already identified as a regulator of the GAT-1 transporter is the Brain Derived Neurotrophic Factor (BDNF). The BDNF is a neurotrophic factor that plays an important role in the growth process, survival and neuronal differentiation, leading to long-term structural and molecular changes that are crucial for both the development and the synaptic function and plasticity in adults (7).

BDNF acts via the activation of Tyrosine Kinase B (TrkB) that presents itself through distinct isoforms: “full-length” isoform (TrkB-fl) showing tyrosine kinase domains, and a truncated isoform (TrkB-t) not showing those domains. BDNF encourages GABA reuptake due to increased GAT-1 expression in the plasma membrane in neuronal primary cultures (5). Nevertheless, in presynaptic nervous terminals, it leads to reduced GABA reuptake through the same transporter (8). These two results suggest that this molecule acts at a very local level and leads to reduced GABA reuptake in the nervous terminal, accelerating its reuptake in extrasynaptic regions. The activation of adenosine A2A receptors has been perceived as the keystone in the “rapid” effects of
BDNF. Among others, there is the fact that the effect of BDNF in synaptic transmission depends on the activation of the aforementioned adenosine receptors (9).

Astrocytes are the largest class of glial cells found in the brain of mammals and have an extremely important role in synaptic transmission, inasmuch as they contribute to the processing of information trasnsmitted synaptically. This is due to the fact that they control the composition of the extracelluar environment, the amount of neurotransmitters in the synaptic cleft, and the communication among astrocytes or between astrocytes and neurons (10). These cells play a major role in regulating extracellular GABA levels (11), and yet very little has been written with regard to GABA transporters control in astrocytes.

Accordingly, the research carried out aimed to study the BDNF effect over the GAT-1transporter in astrocytes, as well as investigate the mechanisms inherent to the BDNF effect.

The present work enabled us to note that BDNF increases GABA GAT-1 receptor mediated reuptake in astrocyte primary cultures, and that this is due to an increase in the transporter’s Vmax. The BDNF effect involves the truncated form of the TrkB receptor, the former being attached to a non-classical pathway of PLC-?/PKC-? and Erk/MAP kinases. The effect described above requires that A2A adenosine receptors are active, since the presence of this receptor’s selective antagonists has been abolished. Given that Vmax increase correlates with a growing number of transporters in the plasma membrane, we subsequently evaluated the possibility of increased GAT-1 transporter when cells are treated with BDNF. Accordingly, in order to ascertain if the BDNF effect correlated with GAT-1 trafficking into the cell membrane, we created a functional rat GAT-1 transporter mutant (rGAT-1), introduced the hemagglutinin epitope (HA) into the second extracellular loop of the transporter and infected astrocytes with the said mutant.

We noted increased HA-rGAT-1 expression in the plasma membrane after treating cells with BDNF. Through biotinylation experiments on astrocytes that overexpressed rGAT-1, increased rGAT-1 after BDNF treatment was equally observed.

These results allow us to conclude that BDNF induces the translocation of the GAT-1 transporter into astrocyte plasma membrane, and that this has functional consequences. Thus, it may also be concluded that BDNF plays an active role in GABA reuptake at both synaptic and extrasynaptic levels, ultimately influencing neuronal excitability.

 

Sandra Henriques Vaz
Institute of Pharmacology and Neurosciences of the Faculty of Medicine
Neuroscience Unit of the Institute of Molecular Medicine
svaz@fm.ul.pt

_________________
Bibliography

1. Gether, U., Andersen, P. H., Larsson, O. M., and Schousboe, A. (2006) Trends Pharmacol Sci27, 375-383
2. Lee, T. S., Bjornsen, L. P., Paz, C., Kim, J. H., Spencer, S. S., Spencer, D. D., Eid, T., and de Lanerolle, N. C. (2006) Acta Neuropathol 111, 351-363
3. Iversen, L. (2006) Br J Pharmacol 147 Suppl 1, S82-88
4. Deken, S. L., Wang, D., and Quick, M. W. (2003) J Neurosci 23, 1563-1568
5. Law, R. M., Stafford, A., and Quick, M. W. (2000) J Biol Chem 275, 23986-23991
6. Cristovao-Ferreira, S., Vaz, S. H., Ribeiro, J. A., and Sebastiao, A. M. (2009) J Neurochem109, 336-347
7. Vicario-Abejon, C., Owens, D., McKay, R., and Segal, M. (2002) Nat Rev Neurosci 3, 965-974
8. Vaz, S. H., Cristovao-Ferreira, S., Ribeiro, J. A., and Sebastiao, A. M. (2008) Brain Res 1219, 19-25
9. Sebastiao, A. M., Assaife-Lopes, N., Diogenes, M. J., Vaz, S. H., and Ribeiro, J. A. (2010) Biochim Biophys Acta
10. Halassa, M. M., and Haydon, P. G. (2010) Annu Rev Physiol 72, 335-355
11. Kirmse, K., Kirischuk, S., and Grantyn, R. (2009) Synapse 63, 921-929

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Index - News # 20 | mar/abr. 2011
 Editorial Note
 Camilla, Duchess of Cornwall, visit IMM
 New@FMUL New Editorial Team
 The Harvard Medical School Portugal Program brings health to social networks.
 What now, Portugal?” – RTP Programme “Pros and Cons” at the University of Lisbon
 SPUL organises the first training course
 Interview with Professor Alexandre Ribeiro – Pharmacology and Neuroscience Institute’s Director
 FUTURÁLIA: “This is your life! Find your own way”
 Cid dos Santos Cultural Soiree
 Curricular Reform at the Faculty of Medicine of the University of Lisbon
 Ceremony of the 100th Anniversary of the University of Lisbon
 Consentimento informado e Esclarecido – Debates de Reflexão da Associação dos Antigos Alunos FMUL
 The Administrative Branches Coordinating Unit – presents the project to FMUL’s Newsletter
 Book of the Month
 3rd Post-Graduate Refresher Course “Ethical Decisions In End Of Life” – 14-16 April
 Provas Académicas na Faculdade de Medicina da Universidade de Lisboa
 Lecturers’ Participation in Academic Examinations Panels in other institutions by 24 March 2011
 Scientific Research Projects 2009/2010 – Neurosciences Area
 ONCOLOGY SERIES Seminars- Interview with Professor Luís Costa
 Publications FMUL/HSM/IMM
 Modulation of hippocampal GABAergic transmission by adenosine – Summary of ongoing project 
 Regulation of the GAT-1 transporter in neuronal cells: action of the Brain-Derived Neurotrophic Fact
 Modulation of GABA transport – Effect of adenosine on GAT-1 and GAT-3 mediated GABA reuptake  
 Meta-modulation of hippocampal excitatory transmission by adenosine in rats: from a physiological situation to hypoxic/ischemic insult 
 Relationship between depression and dementia: clinical and animal behaviour studies
 Neuroscience Debate in the Second Conference Falar Global (Talking Globally)
 Biorrythms and School Underachievement: a few opinions and thoughts
 Social networks and social movements
 Sports, Culture and Wellness at the University of Lisbon – Activities in April
 The European Documentation Center of The University of Lisbon publishes Newsletter
 Instituto Confúcio
 Science and Health Research
 Dia Mundial da Voz – 16 de Abril
 XII Meeting of the Portuguese Society for Neurosciences – May 26-28, 2011
 Seminar Oncology Series – Targeted Therapy for Advanced Renal Cell Carcinoma – 5 de Maio
 Prémio Água é Saúde – Candidaturas até 1 de Junho
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100 AnosPropriedade e Edição: Faculdade de Medicina da Universidade de Lisboa NIPC: 502662875  Periodicidade: Mensal  Diretor: Prof. Doutor Fausto J. Pinto Conselho Editorial: Prof. Doutor Fausto J. Pinto, Profª. Doutora Ana Sebastião, Prof. Doutor Mamede de Carvalho, Prof. Doutor António Vaz Carneiro, Prof. Doutor Miguel Castanho, Dr. Luís Pereira  Equipa Editorial:  Ana Raquel Moreira, Cristina Bastos, Isabel Varela, Joana Sousa, Maria de Lurdes Barata, Rui Gomes, Sónia Teixeira  Colaboração:  Gabinete de Relações Públicas, Internacionais e Comunicação  Versão Inglesa: AP|PORTUGAL- Language Services  Conceção: Metatexto, Lda. e-mail: news@medicina.ulisboa.pt  Sede do Editor e Sede da Redação: Avenida Prof. Egas Moniz, 1649-028 Lisboa Estatuto Editorial Anotado na ERC 

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