Assistant Professor of Biological Sciences.
Molecular Neuroscience, Membrane Contact Sites, Electrophysiology, Intracellular Signaling, Antibodies
Brain neurons use electrical signals to communicate. The neuronal cell body (or soma) collects and integrates electrical signals from multiple synaptic inputs. This prompts the initiation of new electrical signals, modification of gene expression, and alterations in cellular metabolism to support the overall function and adaptability of the neuron.
We study the protein complexes that detect and decipher electrical signals in the soma, with an emphasis on those found at contact sites between endoplasmic reticulum (ER) and the plasma membrane (PM). ER-PM junctions are especially abundant in the soma and provide a platform for compartmentalized crosstalk between electrical and intracellular signaling systems. We aim to define the physiological impact of signaling from these sites and develop an atlas of the distinct classes of ER-PM junctions in brain neurons.
Our research takes a multi-disciplinary approach, employing techniques such as electrophysiology and fluorescence microscopy with biochemical methods, including protein mass spectrometry and the generation and use of novel antibodies. Our ultimate objective is to improve fundamental knowledge of neuronal function. We also hope that this work will lead us to a better understanding of how disruption of proteins that function at these sites contributes to human disease. Specific projects towards these goals are focused on:
Defining the cellular functions of stacked subsurface cisternae
ER at neuronal ER-PM contacts often forms large, flattened vesicles called subsurface cisternae. A subset of neuronal ER-PM junctions are associated with parallel stacks of subsurface cisternae. Although these discrete ER structures found in neurons throughout the brain were discovered over 60 years ago, their cellular functions remain unclear. Our work suggests that these ER stacks comprise organelles that detect electrical signals and translate them into a biochemical form that the cell's intracellular signaling machinery can understand, activating key cellular responses such as gene transcription. We are working to understand how these unique structures are formed and organized, and their roles in neuronal function.
Understanding the role of signaling complexes at ER-PM junctions in adjusting electrical activity
Plasma membrane- and ER-localized ion channels are highly clustered at ER-PM contacts in brain neurons. We are working to discover the molecular relationships between these channels and the other signaling proteins targeted to these sites that help neurons interpret and transmit electrical signals.
References (Selected Publications)
- Vierra, N. C. et al. Neuronal ER-plasma membrane junctions couple excitation to Ca(2+)-activated PKA signaling. Nat Commun 14, 5231 (2023). https://doi.org:10.1038/s41467-023-40930-6
- Vierra, N. C., O'Dwyer, S. C., Matsumoto, C., Santana, L. F. & Trimmer, J. S. Regulation of neuronal excitation-transcription coupling by Kv2.1-induced clustering of somatic L-type Ca(2+) channels at ER-PM junctions. Proc Natl Acad Sci U S A 118 (2021). https://doi.org:10.1073/pnas.2110094118
- Vierra, N. C., Kirmiz, M., van der List, D., Santana, L. F. & Trimmer, J. S. Kv2.1 mediates spatial and functional coupling of L-type calcium channels and ryanodine receptors in mammalian neurons. Elife 8 (2019). https://doi.org:10.7554/eLife.49953
- Kirmiz, M., Vierra, N. C., Palacio, S. & Trimmer, J. S. Identification of VAPA and VAPB as Kv2 channel-interacting proteins defining endoplasmic reticulum-plasma membrane junctions in mammalian brain neurons. J Neurosci 38, 7562-7584 (2018). https://doi.org:10.1523/JNEUROSCI.0893-18.2018