A recently published study in Science Journal presented a fantastic new tool for neuroscience research. Scientists at Peking University, led by Huan Wang, have unveiled an advancement in the study of neuronal communication, shedding (fluorescent) light on the activity of neuropeptides.
Neurotransmitters, the messengers of the nervous system, come in two varieties: fast and slow. Fast neurotransmitters elicit immediate on or off responses in the next neuron, while slow neurotransmitters, including various neuropeptides, signal through G-protein coupled receptors (GPCRs). When activated by their neuropeptide ligand, the transmembrane GPCRs initiate cascades of molecular actions within a cell. One prevailing hypothesis posits that slow neuropeptides, released alongside fast neurotransmitters, assist in recalibrating and optimizing their faster counterparts' binary communication.
Through a pioneering innovation, Wang et al. developed GRABs (G protein-coupled receptor activation-based biosensors), a biosensor technology designed to detect neuropeptides with high spatial and temporal resolution. These sensors, sensitive to nanomolar concentrations associated with neuropeptide binding, provide a glimpse into the previously obscured actions of neuropeptide.
The researchers created a GRAB for a neuropeptide of interest by inserting a fluorophore into the third transmembrane loop of that neuropeptide's GPCR. When the neuropeptide binds to the GPCR and changes the shape of the protein, the fluorescence increases measurably. Scientists can apply this versatile tool to almost any GPCR a neuropeptide activates. Wang et al. utilized laboratory-designed viruses to deliver these fluorophore-containing GPCRs into different mouse brain areas, enabling the detection of endogenous neuropeptide release.
Taking this innovative technology a step further, Wang et al. investigated the expression of neuropeptides during mouse learning and acute stress, recording the behavior-associated release of neuropeptides. Previous research had already linked somatostatin (SST) with learning, but Wang et al. discovered dynamic changes in SST release during conditioned learning in freely moving mice.
Furthermore, the study uncovered that while corticotropin-releasing hormone (CRH) was released throughout the body to trigger a stress response, it affected local circuits along the way. The researchers also confirmed that non-neuronal cells also release neuropeptides, presumably for long-range signaling.
GRAB sensors are a significant leap forward, allowing the recording of neuropeptide release from specific brain regions. Using this tool, new research designs can better answer questions concerning the intricacies of neuronal communication and the roles of neuropeptides in both health and disease. This innovative technology has the potential to revolutionize the study of neuropeptide signaling not only in the brain but throughout the entire body, providing an essential new tool for unraveling the mysteries of cellular communication.
Sources: Science (1)(2)
