In a recent study, published in the journal Proceedings of the National Academy of Sciences, an interdisciplinary team of scientists from The Hong Kong University of Science and Technology (HKUST) and The Chinese University of Hong Kong (CUHK) discovered that two large protein kinases, ATM and ATR, cooperate to help establish the go/stop balance in human brains.

"We show that ATM and ATR regulate each other's levels in the brain. When ATM levels drop, ATR levels increase and the reverse. Just as important, regular brain activity also changes the levels of the two proteins," said Aifang Cheng, first author of the paper.

"This means that neuronal activity and the two kinases are in a dynamic 'conversation' that helps to keep the appropriate balance between excitation and inhibition (known as the E/I balance) by adjusting the levels of ATM and ATR," Cheng added. 

The team found that the two proteins divide up responsibilities for the 'go' and 'stop' functions. ATM helps regulate only excitatory events while ATR helps regulate only the inhibitory ones; this is achieved by controlling the movement of tiny synaptic vesicles in the neuronal synapse.

Utilizing super-resolution microscopy offered by the Super-Resolution Imaging Center (SRIC) at HKUST, the researchers were able to view the cellular location of the two kinases at ultra-high magnification.

The groups had previously worked together to show that ATM was found on synaptic vesicles, but no one had ever looked for ATR. Combining their efforts for the second time, the team was able to show that ATR was also on synaptic vesicles (identified with a protein called VAMP2).

"One of the challenges we faced was that even at high magnification, all vesicles look pretty much alike," said Du Shengwang, Associate Director of SRIC. "To provide differentiation, we developed a three-color version of our super-resolution system, which allowed the team to prove that ATM and ATR were never found on the same VAMP2-containing synaptic vesicle."

Cheng also measured the size of the synaptic vesicles, and she discovered that the vesicles without ATM were bigger than normal, a hint that there was a problem with the composition of the synaptic membrane.

"The new findings are in the realm of basic research, but they have important implications for human disease," said Karl Herrup, Chair Professor and Head of the Division of Life Science at HKUST, Director of the SRIC.

"Epilepsy, for example, is a condition where one of the problems is that inhibition fails. As our findings would predict, humans with too little ATR have a problem with epilepsy, while people with ATM deficiency by contrast are ataxic — a reduced ability to make finely controlled movements and keep the proper E/I ratio." 

"This means that there is a yin-yang relationship between ATM and ATR. And really, this is only the beginning. We believe that our work has potential relevance to a much broader range of neurologic conditions."