Research
Ion Channels in Health and Disease
Ion channels are transmembrane proteins that are found in all excitable cells, and are the key regulators of the electrochemical signaling essential to intra- and intercellular communication. In neurons of the brain, voltage-gated and ligand-gated channels are responsible for receiving, combining, propagating and delivering information throughout the neural network. The expression, assembly, function and subcellular distribution of channels are tightly controlled and highly specific. Perturbation or malfunction at any of these levels of control can result in a significant alteration of neuronal circuit activity and may culminate in major changes to brain function and disease. Ion channels have been found to be directly responsible in brain-associated conditions such as addiction, epilepsy, and cancer.
Feedback loop of animal behavior, ion channel activity, and neuronal circuit interactions. Image: Peters, 2018
Nicotine Dependence: Channels, Circuits, And Behaviors
In the Peters Lab, we are especially interested in how the regulation and function of ion channels can be disturbed in order to cause and maintain nicotine dependence. Nicotine is a potent agonist of the eponymous nicotinic acetylcholine receptors (nAChR), a family of ligand-gated ion channels with widespread distribution throughout the central nervous system and skeletal muscles. Nicotine can act as an activator, desensitizer and molecular chaperone of nAChR, and produces both acute and chronic effects on neurons where the target channels are expressed.
NAChR regulate cellular signaling through both voltage- and calcium-dependent mechanisms. Aberrant signaling due to the presence of nicotine can modify a wide range of cellular processes involving nAChR, as well as other genes and proteins interacting with or downstream of them. Untangling how and where these changes occur to ultimately produce behaviors associated with nicotine dependence is a major focus of our research.
Furthermore, vertebrate nAChR are pentameric channels built from tightly regulated combinations of 17 different genes of the CHRN(X) family. Correct expression, assembly, folding, distribution, and ultimately function depend on the specific properties of these individual family members, and are critical in maintaining neuronal function and in governing the channel's response to nicotine. In particular, the incorporation of rare and/or silent subunits into the nAChR pentamer (eg: CHRNA5 and CHRNA6) can produce major effects on all channel properties, and parsing the roles of these subunits in normal function and on nicotine-influenced perturbations is a key unanswered question.
We at the Peters Lab seek to understand how the properties of these channels, as well as their interactors and downstream targets, dictate their function and subcellular distribution. Additionally, we are exploring how these properties then regulate circuit activity and behavior associated with nicotine seeking or nicotine avoidance. Our lab utilizes molecular biology and imaging, electrophysiology, optogenetics and photometry, and behavioral assays in rodent models to answer these questions with an eye towards informing therapeutic strategies to combat nicotine addiction.
Schematic of stereotaxic injection followed by fiber photometric studies. Image: Leopold AV, Shcherbakova DM and Verkhusha VV (2019) Fluorescent Biosensors for Neurotransmission and Neuromodulation: Engineering and Applications. Front. Cell. Neurosci. 13:474. doi: 10.3389/fncel.2019.00474
Chloride Ions: Regulators of Cell Cycle Progression & Cancer MOtility
Another interest of the Peters Lab is understanding the role that ion channels play in cancer cell physiology. Cancer is a broad term used to describe diseases where cell growth and division proceed unchecked by normal cellular control pathways. Cell cycle progression and cell migration (in normal and tumor cell types) are critically dependent on external and internal cellular environments, including the chemical and electrical gradients produced across the cell membrane. Transmembrane ion channels are ideally positioned to regulate and react to these gradients, and considerable evidence shows that distinct complements of ion channels are upregulated in different cancer types.
In our lab, we are especially interested in how chloride channels regulate tumor cell physiology in cancer cells derived from epithelial tissue. We use a combination of molecular biology, pharmacology, live cell imaging and electrophysiology to probe these questions with the aim of developing chloride channels as potential targets for therapeutic interventions against cancer.
Sequential imaging of prostate cancer cell cultures grown overnight, showing delayed mitosis in cells treated with a TMEM16A antagonist when compared to untreated cells. Image: Netherton (2021), Unpublished