Flipping a Protein Switch to Illuminate Brain Functions

Summary: Researchers have been able to selectively activate glutamate receptors.

Source: Kyoto University.

Pacman-shaped receptor’s ‘bite’ sheds light on learning and memory processes.

What goes on inside the brain when we learn new things? Much still remains wrapped in mystery, but scientists have found a way to examine this at the molecular level.

Researchers in Japan have engineered an artificial switch that could let scientists turn individual neurotransmitter receptors on and off. Shedding light on these receptors’ role in memory formation could contribute to the development of new drugs for neurological diseases, including Alzheimer’s, Parkinson’s, and ALS.

Neurotransmitter receptors help relay information from neuron to neuron. “Investigating the functions of various neurotransmitter receptors could be immensely useful, because a majority of drugs on the market target them,” says lead author Ryou Kubota of Kyoto University. “But with so many similarly-structured proteins in the membrane, it’s been extremely difficult to determine which receptors do what.

“Discovering the functions of each neurotransmitter receptor in the brain could help us understand how we learn and acquire memory; to do that, it’s crucial to be able to activate them selectively.”

In the study, published in Nature Chemistry, the team succeeded in selectively activating glutamate receptors, which are pacman-shaped neutrotransmitter receptors known to be involved in memory formation.

Image shows the pacman shaped protein.
Researchers in Japan have engineered an artificial switch that could let scientists turn individual neurotransmitter receptors on and off. Shedding light on these receptors’ role in memory formation could contribute to the development of new drugs for neurological diseases, including Alzheimer’s, Parkinson’s, and ALS. NeuroscienceNews.com image is credited to Eiri Ono/Kyoto University.

Membrane proteins change in shape when they become active. For pacman-shaped glutamate receptors, activation happens when they “bite”. The team genetically engineered glutamate receptors to include switches forcing activation and deactivation. “The switch comes in the shape of two ‘clips’ on what would be the upper and lower lips of pacman,” explains Kubota. “When we tell the clips to bind together, we force the glutamate receptor to activate.”

The current study only reports outcomes with glutamate receptors, but the authors say that their method also shows promise with other kinds of membrane receptors. “Even within glutamate receptors there are subtypes, and within those subtypes there are further distinctions. This time we were able to distinguish and selectively activate each subtype,” remarks Kubota.

“We’ve observed with further experiments that this method is generally applicable to other membrane receptors as well. By refining the technique, we hope that the discovery of each receptor’s functions will advance our understanding of the brain’s mechanisms.”

About this genetics research article

Funding: Japan Science and Technology Agency, Ministry of Education, Culture, Sports, Science and Technology in Japan funded the study.

Source: Anna Ikarashi – Kyoto University
Image Source: This NeuroscienceNews.com image is credited to Eiri Ono/Kyoto University.
Original Research: Abstract for “Allosteric activation of membrane-bound glutamate receptors using coordination chemistry within living cells” by Shigeki Kiyonaka, Ryou Kubota, Yukiko Michibata, Masayoshi Sakakura, Hideo Takahashi, Tomohiro Numata, Ryuji Inoue, Michisuke Yuzaki and Itaru Hamachi in Nature Chemistry. Published online June 27 2016 doi:10.1038/nchem.2554

Cite This NeuroscienceNews.com Article

[cbtabs][cbtab title=”MLA”]Kyoto University. “Flipping a Protein Switch to Illuminate Brain Functions.” NeuroscienceNews. NeuroscienceNews, 27 June 2016.
<https://neurosciencenews.com/pacman-protein-memory-4579/>.[/cbtab][cbtab title=”APA”]Kyoto University. (2016, June 27). Flipping a Protein Switch to Illuminate Brain Functions. NeuroscienceNews. Retrieved June 27, 2016 from https://neurosciencenews.com/pacman-protein-memory-4579/[/cbtab][cbtab title=”Chicago”]Kyoto University. “Flipping a Protein Switch to Illuminate Brain Functions.” https://neurosciencenews.com/pacman-protein-memory-4579/ (accessed June 27, 2016).[/cbtab][/cbtabs]


Abstract

Allosteric activation of membrane-bound glutamate receptors using coordination chemistry within living cells

The controlled activation of proteins in living cells is an important goal in protein-design research, but to introduce an artificial activation switch into membrane proteins through rational design is a significant challenge because of the structural and functional complexity of such proteins. Here we report the allosteric activation of two types of membrane-bound neurotransmitter receptors, the ion-channel type and the G-protein-coupled glutamate receptors, using coordination chemistry in living cells. The high programmability of coordination chemistry enabled two His mutations, which act as an artificial allosteric site, to be semirationally incorporated in the vicinity of the ligand-binding pockets. Binding of Pd(2,2′-bipyridine) at the allosteric site enabled the active conformations of the glutamate receptors to be stabilized. Using this approach, we were able to activate selectively a mutant glutamate receptor in live neurons, which initiated a subsequent signal-transduction pathway.

“Allosteric activation of membrane-bound glutamate receptors using coordination chemistry within living cells” by Shigeki Kiyonaka, Ryou Kubota, Yukiko Michibata, Masayoshi Sakakura, Hideo Takahashi, Tomohiro Numata, Ryuji Inoue, Michisuke Yuzaki and Itaru Hamachi in Nature Chemistry. Published online June 27 2016 doi:10.1038/nchem.2554

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