ATM and ATR play complementary roles in the behavior of excitatory and inhibitory vesicle populations

Proc Natl Acad Sci U S A. 2018 Jan 9;115(2):E292-E301. doi: 10.1073/pnas.1716892115. Epub 2017 Dec 26.


ATM (ataxia-telangiectasia mutated) and ATR (ATM and Rad3-related) are large PI3 kinases whose human mutations result in complex syndromes that include a compromised DNA damage response (DDR) and prominent nervous system phenotypes. Both proteins are nuclear-localized in keeping with their DDR functions, yet both are also found in cytoplasm, including on neuronal synaptic vesicles. In ATM- or ATR-deficient neurons, spontaneous vesicle release is reduced, but a drop in ATM or ATR level also slows FM4-64 dye uptake. In keeping with this, both proteins bind to AP-2 complex components as well as to clathrin, suggesting roles in endocytosis and vesicle recycling. The two proteins play complementary roles in the DDR; ATM is engaged in the repair of double-strand breaks, while ATR deals mainly with single-strand damage. Unexpectedly, this complementarity extends to these proteins' synaptic function as well. Superresolution microscopy and coimmunoprecipitation reveal that ATM associates exclusively with excitatory (VGLUT1+) vesicles, while ATR associates only with inhibitory (VGAT+) vesicles. The levels of ATM and ATR respond to each other; when ATM is deficient, ATR levels rise, and vice versa. Finally, blocking NMDA, but not GABA, receptors causes ATM levels to rise while ATR levels respond to GABA, but not NMDA, receptor blockade. Taken together, our data suggest that ATM and ATR are part of the cellular "infrastructure" that maintains the excitatory/inhibitory balance of the nervous system. This idea has important implications for the human diseases resulting from their genetic deficiency.

Keywords: E/I balance; clathrin; endocytosis; neurodegeneration; vesicle trafficking.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Cells, Cultured
  • Gene Expression Regulation
  • Mice
  • Mice, Knockout
  • Neurons / physiology*
  • Synapses / physiology
  • Transport Vesicles / physiology*
  • Vesicle-Associated Membrane Protein 2


  • Vesicle-Associated Membrane Protein 2
  • vesicle-associated membrane protein 2, mouse
  • Atr protein, mouse
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse