Ion channel-associated macromolecular complexes at ER-PM junctions form independent Ca2+ signaling microdomains in the soma, as revealed by a Ca2+ indicator enriched at ER-PM contact sites (GCaMP3-Kv2.1) expressed in a rat hippocampal neuron.
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Electron micrograph of stacked subsurface cisternae (SSCs) in the soma of a mouse brain neuron (neocortex). Glial cells can frequently be found contacting neurons at somatic ER-PM junctions. Image adapted with permission from the Atlas of Ultrastructural Neurocytology.
Compartmentalized signaling in the soma enables diverse biochemical responses to action potentials
Brain neurons communicate through electrical signals that can instruct a neuron to modify its activity and structure. This enables the nervous system to learn from the environment. However, our understanding of how neurons convert electrical signals into a biochemical response remains limited, particularly in the cell body where gene expression and ion channel function dictate neuronal activity. We study the protein complexes that detect and decipher these electrical signals, 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 seek to understand the molecular components and mechanisms that mediate signal transmission at neuronal ER-PM contacts and in some cases play a dual structural role in organizing the ER-PM junction itself. 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. 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 data 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 the ion channels and the other signaling proteins targeted to these sites that help neurons interpret and transmit electrical signals.
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