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Chemical genetic identification of GAK substrates reveals its role in regulating Na(+)/K(+)-ATPase
Cyclin G–associated kinase (GAK) is a ubiquitous serine/threonine kinase that facilitates clathrin uncoating during vesicle trafficking. GAK phosphorylates a coat adaptor component, AP2M1, to help achieve this function. GAK is also implicated in Parkinson's disease through genome-wide associati...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Life Science Alliance LLC
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312924/ https://www.ncbi.nlm.nih.gov/pubmed/30623173 http://dx.doi.org/10.26508/lsa.201800118 |
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author | Lin, Amy W Gill, Kalbinder K Castañeda, Marisol Sampedro Matucci, Irene Eder, Noreen Claxton, Suzanne Flynn, Helen Snijders, Ambrosius P George, Roger Ultanir, Sila K |
author_facet | Lin, Amy W Gill, Kalbinder K Castañeda, Marisol Sampedro Matucci, Irene Eder, Noreen Claxton, Suzanne Flynn, Helen Snijders, Ambrosius P George, Roger Ultanir, Sila K |
author_sort | Lin, Amy W |
collection | PubMed |
description | Cyclin G–associated kinase (GAK) is a ubiquitous serine/threonine kinase that facilitates clathrin uncoating during vesicle trafficking. GAK phosphorylates a coat adaptor component, AP2M1, to help achieve this function. GAK is also implicated in Parkinson's disease through genome-wide association studies. However, GAK's role in mammalian neurons remains unclear, and insight may come from identification of further substrates. Employing a chemical genetics method, we show here that the sodium potassium pump (Na(+)/K(+)-ATPase) α-subunit Atp1a3 is a GAK target and that GAK regulates Na(+)/K(+)-ATPase trafficking to the plasma membrane. Whole-cell patch clamp recordings from CA1 pyramidal neurons in GAK conditional knockout mice show a larger change in resting membrane potential when exposed to the Na(+)/K(+)-ATPase blocker ouabain, indicating compromised Na(+)/K(+)-ATPase function in GAK knockouts. Our results suggest a modulatory role for GAK via phosphoregulation of substrates such as Atp1a3 during cargo trafficking. |
format | Online Article Text |
id | pubmed-6312924 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Life Science Alliance LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-63129242019-01-08 Chemical genetic identification of GAK substrates reveals its role in regulating Na(+)/K(+)-ATPase Lin, Amy W Gill, Kalbinder K Castañeda, Marisol Sampedro Matucci, Irene Eder, Noreen Claxton, Suzanne Flynn, Helen Snijders, Ambrosius P George, Roger Ultanir, Sila K Life Sci Alliance Research Articles Cyclin G–associated kinase (GAK) is a ubiquitous serine/threonine kinase that facilitates clathrin uncoating during vesicle trafficking. GAK phosphorylates a coat adaptor component, AP2M1, to help achieve this function. GAK is also implicated in Parkinson's disease through genome-wide association studies. However, GAK's role in mammalian neurons remains unclear, and insight may come from identification of further substrates. Employing a chemical genetics method, we show here that the sodium potassium pump (Na(+)/K(+)-ATPase) α-subunit Atp1a3 is a GAK target and that GAK regulates Na(+)/K(+)-ATPase trafficking to the plasma membrane. Whole-cell patch clamp recordings from CA1 pyramidal neurons in GAK conditional knockout mice show a larger change in resting membrane potential when exposed to the Na(+)/K(+)-ATPase blocker ouabain, indicating compromised Na(+)/K(+)-ATPase function in GAK knockouts. Our results suggest a modulatory role for GAK via phosphoregulation of substrates such as Atp1a3 during cargo trafficking. Life Science Alliance LLC 2018-12-31 /pmc/articles/PMC6312924/ /pubmed/30623173 http://dx.doi.org/10.26508/lsa.201800118 Text en © 2018 Lin et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Articles Lin, Amy W Gill, Kalbinder K Castañeda, Marisol Sampedro Matucci, Irene Eder, Noreen Claxton, Suzanne Flynn, Helen Snijders, Ambrosius P George, Roger Ultanir, Sila K Chemical genetic identification of GAK substrates reveals its role in regulating Na(+)/K(+)-ATPase |
title | Chemical genetic identification of GAK substrates reveals its role in regulating Na(+)/K(+)-ATPase |
title_full | Chemical genetic identification of GAK substrates reveals its role in regulating Na(+)/K(+)-ATPase |
title_fullStr | Chemical genetic identification of GAK substrates reveals its role in regulating Na(+)/K(+)-ATPase |
title_full_unstemmed | Chemical genetic identification of GAK substrates reveals its role in regulating Na(+)/K(+)-ATPase |
title_short | Chemical genetic identification of GAK substrates reveals its role in regulating Na(+)/K(+)-ATPase |
title_sort | chemical genetic identification of gak substrates reveals its role in regulating na(+)/k(+)-atpase |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312924/ https://www.ncbi.nlm.nih.gov/pubmed/30623173 http://dx.doi.org/10.26508/lsa.201800118 |
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