Researchers from the University of Birmingham (UK) and the University of Würzburg (Germany) have used super-resolution microscopy to examine a G protein-coupled receptor (GPCR) that mediates neural transmission.
The study, published in Science Advances, reveals evidence regarding how these receptors are organized within the brain; information that could potentially aid our understanding of the development of neurodegenerative disorders such as Alzheimer’s and Parkinson’s.
GPCRs are involved in cell communication behind virtually all physiological processes in the body. In order to develop effective treatments for conditions such as Parkinson’s and Alzheimer’s, in which cells are unable to communicate effectively, it is important for us to be able to understand how these receptors work under normal conditions.
While previous research has investigated other types of receptors, until now very little has been known about the organization of metabotropic glutamate receptors (mGluR4) and other GPCRs in the brain.
In this study, researchers used an innovative super-resolution microscopy method termed dSTORM to produce images of mGluR4 receptors in the brain with a resolution of approximately 10 nm.
Using these nanoscale images, the team observed that the receptors are not randomly located within synapses, as previously assumed, but rather are located in highly organized ‘nanodomains,’ sitting in close proximity to the molecules that they regulate.
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The researchers postulate that this pattern of organization allows the receptors to physically interact with their targets in order to regulate neural communication.
“By understanding how receptors such as mGluR4 work, we hope to be able to design innovative drugs capable of modulating their function. Our findings could help better understand neurological and neurodegenerative disorders and develop new treatments for diseases such as Parkinson’s or Alzheimer’s,” commented Davide Calebiro (University of Birmingham).
“We hope this research could pave the way to further studies aimed at explaining the functional consequences of the high spatial organization of synaptic GPCRs we have uncovered. In addition, it will enable other groups to apply similar methods to investigate the nanoscale organization of molecules involved in other fundamental biological processes,” Calebiro added.
The team is planning to study the movement of these receptors as the next stage in their research.
“So far we have obtained static pictures, but we suspect these structures to be highly dynamic. At our Centre of Membrane Proteins and Receptors (COMPARE), a joint venture with the University of Nottingham (UK), we and other researchers are developing highly innovative methods to track single molecules in real time with unprecedented spatio-temporal resolution. We plan to use these methods to investigate the dynamics of receptors and other signalling molecules in neurons and other cells,” concluded Calebiro.
Sources: Siddig S, Aufmkolk S, Doose S et al. Super-resolution imaging reveals the nanoscale organization of metabotropic glutamate receptors at presynaptic active zones. Sci. Advances 6(16), eaay7193 (2020); University of Birmingham. First super-resolution image of tiny brain receptor could give scientists a better understanding of Parkinson’s and Alzheimer’s. Press release: www.birmingham.ac.uk