Chemical Genetic Identification of Cyclin-G-associated kinase (GAK) Substrates Reveals its Role in Regulating Na+/K+-ATPase and Sipa1L1 in Neurons

Recent genetic evidence implicates the serine/threonine kinase cyclin G-associated kinase (GAK) as a Parkinson’s disease risk. However, its role in neuronal function and many downstream effectors remain unclear. Employing a chemical genetics method, we show here that the sodium potassium pump (Na+/K+-ATPase) is a GAK target in the brain. We further show that GAK modulates Na+/K+-ATPase at a novel site affecting both pump localization and function. Whole-cell patch clamp recordings from CA1 pyramidal cells in GAK conditional knockout mice show a larger change in resting membrane potential when exposed to the Na+/K+-ATPase blocker, ouabain, indicating altered Na+/K+-ATPase function in GAK knockouts. Additionally, we show that GAK-deficient neurons have enlarged dendritic spines and we identify the spine associated protein Sipa1L1 (or SPAR) as a GAK target, which may contribute to this effect. Our results reveal novel functions of GAK in neurons.