RT Journal Article SR Electronic T1 Chemical genetic identification of GAK substrates reveals its role in regulating Na+/K+-ATPase JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e201800118 DO 10.26508/lsa.201800118 VO 1 IS 6 A1 Amy W Lin A1 Kalbinder K Gill A1 Marisol Sampedro Castañeda A1 Irene Matucci A1 Noreen Eder A1 Suzanne Claxton A1 Helen Flynn A1 Ambrosius P Snijders A1 Roger George A1 Sila K Ultanir YR 2018 UL https://www.life-science-alliance.org/content/1/6/e201800118.abstract 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.