Mass spectrometry analysis reveals massive insight into neuronal signaling
By Emily Overway
Researchers in the lab of Heidi Hamm, a professor of pharmacology who also holds the Aileen M. Lange and Annie Mary Lyle Chair in Cardiovascular Research, recently published a paper exploring the G protein subunits that interact with the SNARE complex. The work led by first author Yun Young Yim, former graduate student and postdoctoral fellow in the Hamm lab, was published in Science Signaling in December.
We sat down with Hamm and Yim to learn more about this exciting work.
What issue/problem does your research address?
There are three G protein subunits – α, β, and γ. We know a lot about the specificity of G protein α subunits for their cognate G protein-coupled receptors and their downstream effectors, but we know comparatively little about G protein βγ dimers, which regulate synaptic transmission by inhibiting the release of neurotransmitter-containing vesicles from presynaptic neurons. The SNARE complex mediates vesicle exocytosis, the process by which neurons release neurotransmitters into synapses in the neuron. We discovered that Gβγ dimers bind to the SNARE complex to mediate inhibition of exocytosis. Our work identified that particular G protein β and γ subunits bind to the SNARE complex. The analysis provided molecular details about the regulation of synaptic transmission by G protein βγ dimers.
What was unique about your approach to the research?
We used a proteomics-based approach to investigate the interactions occurring within presynaptic neurons. We took advantage of Vanderbilt resources like the proteomics core and the Mass Spectrometry Research Center to accomplish this work.
What were your findings?
Using mice as a model system, we were able to identify several G protein β and γ subunits that mediate the negative modulation of exocytosis. The significance of these studies is that, even though there are multiple types of β and γ subunits, only a subset of them bind to the SNARE complex, providing evidence of specificity for interaction with these effectors.
These studies answer the obvious question of “why are there so many Gβγ subunits?” In essence, they give cells the power to shape different signaling outcomes in different cellular environments. We know from our studies that mice that have the Gβγ-SNARE interaction disabled are resistant to obesity, suggesting that turning down secretion/exocytosis could lead to weight gain. So, this interaction could someday be targeted by a drug to treat metabolic changes leading to obesity.
What do you hope will be achieved with the research results in the short and long terms?
We hope that gaining insight into the specificity of G protein β and γ subunits in vivo will provide a greater understanding of the spectrum of G protein functions. This will help us better understand the regulation of synaptic transmission in healthy individuals and how dysfunction in these mechanisms can lead to neurological diseases.
What are the benefits of this research?
This work may provide insights into the homeostatic regulation of synaptic transmission. This knowledge could be a steppingstone to improved treatments for neurological disorders.
Where is this research taking you next? What will you personally be doing, or how will other researchers build on this work?
Next, the lab will look at the specificity of the G protein βγ dimers’ interaction with other βγ effectors. We will use similar methods to determine if there is specificity of βγ binding to other effectors.
This work was supported by the National Institutes of Health.
The paper “Specificities of Gβγ subunits for the SNARE complex before and after stimulation of α2a-adrenergic receptors” was published online in Science Signaling on December 21, 2021.