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Life Sci Alliance. 2018 Dec 31;1(6):e201800118. doi: 10.26508/lsa.201800118. eCollection 2018 Dec.

Chemical genetic identification of GAK substrates reveals its role in regulating Na+/K+-ATPase.

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Kinase and Brain Development Lab, The Francis Crick Institute, London, United Kingdom.
Mass Spectrometry Platform, The Francis Crick Institute, London, United Kingdom.
Protein Purification Facility, The Francis Crick Institute, London, United Kingdom.


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.

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