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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.

Author information

1
Kinase and Brain Development Lab, The Francis Crick Institute, London, United Kingdom.
2
Mass Spectrometry Platform, The Francis Crick Institute, London, United Kingdom.
3
Protein Purification Facility, The Francis Crick Institute, London, United Kingdom.

Abstract

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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