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Research
Chase Carver, Ph.D.
Instructor | Research
Cellular and Integrative Physiology
Channel Inhibition/Excitation of Neurons and Circuits:
Ion channel plasticity occurs throughout the brain and contributes to the control and imbalance of hyperexcitability. My chief interest is the loss of inhibition and hyperexcitation of the hippocampal network that promotes epileptogenesis, which is the conversion of a normal brain to a brain debilitated by recurrent seizures. Although there are currently no approved therapeutics to cure epilepsy or prevent the progression of seizures, a strong focus of my research is to leverage the endogenous ion channel plasticity of neurons to explore new avenues of therapeutic prevention and control of epilepsy. I ardently believe that examination of how neuronal pathways reprioritize signaling is central to improved translational progress in treating epilepsy and neurodegenerative disorders. We use chemoconvulsant and traumatic brain injury models to induce aberrant changes in the cortex and hippocampus that lead to neuronal hyperexcitability. Through patch-clamp electrophysiology and innovative pharmacology to investigate biochemical processes inside the neuron, we have uncovered new mechanisms of voltage-gated ion channel physiology and correlated neurological dysfunction. One aim of current research is to investigate the homeostatic regulation of KCNQ K+ channels and canonical transient receptor potential (TRPC) channels by G protein coupled receptors. This is explored with synaptic connectivity between cholinergic axons and postsynaptic muscarinic acetylcholine receptors in the hippocampus and cortex.
Super Resolution Microscopy:
Stochastic Optical Reconstruction Microscopy (STORM) enables the observation of close-proximity protein complexes that cannot normally be resolved with conventional diffraction-limited microscopy. A number of labs, including ours, have postulated that intimate association of multiple signaling proteins within nanodomains is required to achieve specificity and fidelity in cellular signaling. Our recent works use multi-color STORM, with 2 or 3 different antibody/dye combinations to label proteins, in which we have described the nanodomain proximity of signaling complexes containing ion channels and G protein-coupled receptors, coupled by scaffolding proteins. We are identifying novel and diverse multi-channel super-complexes in central and peripheral nervous system neurons that are dependent on intracellular signaling interactions for both physical and functional association. We have pushed the limits of STORM, and have demonstrated the ability to detect proteins in both the plasma membrane and ER with a resolution of 5-10 nanometers. We have pioneered a novel cluster analysis paradigm that allows us to glean a number of insights of protein interactions at the cell membrane. This is accomplished by a program to teach a computer how to spatially resolve the raw STORM image data of thousands of centroids to derive the make-up of ion channels and protein complexes that are structurally coupled, which can’t be objectively or timely performed by human analysis alone.
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Research & Grants
Techniques:
Brain slice electrophysiology, real-time Ca2+ imaging, and super-resolution imaging to determine how ion channels structurally and functionally couple to control neuronal excitability. Functional studies are paired with both transgenic mouse models and in vivo behavioral study to understand the underpinning neurophysiology. -
Publications
Full publication list can be viewed at:
https://www.ncbi.nlm.nih.gov/myncbi/chase.carver.1/bibliography/public/
Carver CM, Hastings SD, Cook ME, Shapiro MS (2020) Functional responses of the hippocampus to hyperexcitability depend on directed, neuron-specific KCNQ2 K+ channel plasticity. Hippocampus, 30(5): 435-455.
Archer CR, Enslow BT, Carver CM, Stockand JD (2020) Phosphatidylinositol 4,5-bisphosphate directly interacts with the β and γ subunits of the sodium channel ENaC. J Biol Chem, in press.
Shah S, Carver CM, Mullen P, Milne S, Lukacs V, Shapiro MS, Gamper N (2020) Nanodomain Ca2+ signals couple activation of TRPV1 and ANO1 sensory ion channels. Science Signaling, 13(629):eaaw7963.
Grant CV, Carver CM, Hastings SD, Ramachandran K, Muniswamy M, Risinger AL, Beutler JA, Mooberry SL (2019) Triple-negative breast cancer cell line sensitivity to englerin A identifies a new, targetable subtype. Breast Cancer Res Treat 177(2):345-355.
Vigil FA, Bozdemir E, Bugay V, Chun SH, Hobbs M, Sanchez I, Hastings SD, Veraza RJ, Holstein DM, Sprague SM, Carver CM, Cavazos JE, Brenner R, Lechleiter JD, Shapiro MS (2019) Prevention of brain damage after traumatic brain injury by pharmacological enhancement of KCNQ (Kv7, “M-type”) K+ currents in neurons. J Cereb Blood Flow Metab, in press, doi: 10.1177/0271678X19857818.
Carver CM, Shapiro MS (2019) Gq-coupled muscarinic receptor enhancement of KCNQ2/3 channels and activation of TRPC channels in multimodal control of excitability in dentate gyrus granule cells. J Neurosci 39:1566-1587.
Reddy DS, Carver CM, Clossen B, Wu X (2019) Extrasynaptic GABAA receptor-mediated sex differences in antiseizure activity of neurosteroids in status epilepticus and complex partial seizures. Epilepsia 60:730-743.
Whitmire L, Ling L, Bugay V, Carver CM, Timilsina S, Jaffe DB, Shapiro MS, Cavazos JE, Brenner R (2017) Downregulation of KCNMB4 expression and changes in BK channel subtype in hippocampal granule neurons following seizure activity. PLoS ONE 12(11):e0188064. PMC5690595.
Zhang J, Carver CM, Choveau F, Shapiro MS (2016) Clustering and functional coupling of diverse ion channels and signaling proteins revealed by super resolution STORM in neurons. Neuron 92:1-18. PMC5553284.