UZH-Logo

Maintenance Infos

Sustained glutamate receptor activation downregulates GABA(B) receptors by shifting the balance from recycling to lysosomal degradation


Maier, Patrick J; Marin, I; Grampp, T; Sommer, A; Benke, D (2010). Sustained glutamate receptor activation downregulates GABA(B) receptors by shifting the balance from recycling to lysosomal degradation. Journal of Biological Chemistry, 285(46):35606-35614.

Abstract

Metabotropic GABA(B) receptors are abundantly expressed at glutamatergic synapses where they control excitability of the synapse. Here we tested the hypothesis that glutamatergic neurotransmission may feed back to regulate GABA(B) receptors. We found that application of glutamate to cultured cortical neurons led to rapid downregulation of GABA(B) receptors via lysosomal degradation. This effect was mimicked by selective activation of AMPA receptors and further accelerated by co-activation of group I metabotopic glutamate receptors. Inhibition of NMDA receptors, blockade of L-type Ca2+ channels and removal of extracellular Ca2+ prevented glutamate-induced downregulation of GABA(B) receptors, indicating that Ca2+-influx plays a critical role. We further established that glutamate-induced downregulation depends on the internalization of GABA(B) receptors. Glutamate did not affect the rate of GABA(B) receptor endocytosis but led to reduced recycling of the receptors back to the plasma membrane. Blockade of lysosomal activity rescued receptor recycling, indicating that glutamate redirects GABA(B) receptors from the recycling to the degradation pathway. In conclusion, the data indicate that sustained activation of AMPA receptors downregulates GABA(B) receptors by sorting endocytosed GABA(B) receptors preferentially to lysosomes for degradation on expense of recyling. This mechanism may relieve glutamatergic synapses from GABA(B) receptor-mediated inhibition resulting in increased synaptic excitability.

Metabotropic GABA(B) receptors are abundantly expressed at glutamatergic synapses where they control excitability of the synapse. Here we tested the hypothesis that glutamatergic neurotransmission may feed back to regulate GABA(B) receptors. We found that application of glutamate to cultured cortical neurons led to rapid downregulation of GABA(B) receptors via lysosomal degradation. This effect was mimicked by selective activation of AMPA receptors and further accelerated by co-activation of group I metabotopic glutamate receptors. Inhibition of NMDA receptors, blockade of L-type Ca2+ channels and removal of extracellular Ca2+ prevented glutamate-induced downregulation of GABA(B) receptors, indicating that Ca2+-influx plays a critical role. We further established that glutamate-induced downregulation depends on the internalization of GABA(B) receptors. Glutamate did not affect the rate of GABA(B) receptor endocytosis but led to reduced recycling of the receptors back to the plasma membrane. Blockade of lysosomal activity rescued receptor recycling, indicating that glutamate redirects GABA(B) receptors from the recycling to the degradation pathway. In conclusion, the data indicate that sustained activation of AMPA receptors downregulates GABA(B) receptors by sorting endocytosed GABA(B) receptors preferentially to lysosomes for degradation on expense of recyling. This mechanism may relieve glutamatergic synapses from GABA(B) receptor-mediated inhibition resulting in increased synaptic excitability.

Citations

21 citations in Web of Science®
21 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

114 downloads since deposited on 17 Dec 2010
24 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Pharmacology and Toxicology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:7 September 2010
Deposited On:17 Dec 2010 13:14
Last Modified:26 Aug 2016 07:32
Publisher:American Society for Biochemistry and Molecular Biology
ISSN:0021-9258
Additional Information:This research was originally published in: Maier, Patrick J; Marin, I; Grampp, T; Sommer, A; Benke, D (2010). Sustained glutamate receptor activation downregulates GABA(B) receptors by shifting the balance from recycling to lysosomal degradation. The Journal of Biological Chemistry, 285(46):35606-35614. © the American Society for Biochemistry and Molecular Biology.
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1074/jbc.M110.142406
PubMed ID:20826795
Permanent URL: https://doi.org/10.5167/uzh-38327

Download

[img]
Preview
Content: Accepted Version
Filetype: PDF
Size: 6MB
View at publisher

TrendTerms

TrendTerms displays relevant terms of the abstract of this publication and related documents on a map. The terms and their relations were extracted from ZORA using word statistics. Their timelines are taken from ZORA as well. The bubble size of a term is proportional to the number of documents where the term occurs. Red, orange, yellow and green colors are used for terms that occur in the current document; red indicates high interlinkedness of a term with other terms, orange, yellow and green decreasing interlinkedness. Blue is used for terms that have a relation with the terms in this document, but occur in other documents.
You can navigate and zoom the map. Mouse-hovering a term displays its timeline, clicking it yields the associated documents.

Author Collaborations