PT  - JOURNAL ARTICLE
AU  - Amy W Lin
AU  - Kalbinder K Gill
AU  - Marisol Sampedro Castañeda
AU  - Irene Matucci
AU  - Noreen Eder
AU  - Suzanne Claxton
AU  - Helen Flynn
AU  - Ambrosius P Snijders
AU  - Roger George
AU  - Sila K Ultanir
TI  - Chemical genetic identification of GAK substrates reveals its role in regulating Na<sup>+</sup>/K<sup>+</sup>-ATPase
AID  - 10.26508/lsa.201800118
DP  - 2018 Dec 01
TA  - Life Science Alliance
PG  - e201800118
VI  - 1
IP  - 6
4099  - https://www.life-science-alliance.org/content/1/6/e201800118.short
4100  - https://www.life-science-alliance.org/content/1/6/e201800118.full
SO  - Life Sci. Alliance2018 Dec 01; 1
AB  - 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.