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

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) ?-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.

SUBMITTER: Lin AW 

PROVIDER: S-EPMC6312924 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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

Lin Amy W AW   Gill Kalbinder K KK   Castañeda Marisol Sampedro MS   Matucci Irene I   Eder Noreen N   Claxton Suzanne S   Flynn Helen H   Snijders Ambrosius P AP   George Roger R   Ultanir Sila K SK  

Life science alliance 20181231 6

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 pota  ...[more]

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