Calcium; Polycystic Kidney Diseases; Pharmacology; Physiology; Hermeneutics
Cellular & Molecular Physiology: Neurobiology and Physiology of Synapses
Center for Polycystic Kidney Disease Research
The Laboratory of Molecular Hermeneutics is interested in how cells regulate their intracellular calcium concentration. Cells use changes in calcium as a trigger for many cellular events, including cell growth, secretion, contraction, and neurotransmission. We have focused on one aspect of this process, the release of calcium from intracellular stores. We use calcium imaging combined with electrophysiological, biochemical, and molecular techniques to study the classes of calcium release channels known to exist inside virtually all cells: the InsP3-gated channel, the ryanodine receptor, and polycystin-2. Our first goal is to understand the basic question: how is the function of these channels regulated. Our second goal is to use the answers to the first question to understand the loss of calcium regulation observed in disease states as seen in cells from patients with polycystic kidney disease or leading to drug-induced neuropathy. We hypothesize that these abnormalities in function are consequences, at least in part, of altered intracellular calcium homeostasis and that our studies will lead to suitable treatment regimens.
Specialized Terms: Intracellular calcium regulation
- Boehmerle W, Splittgerber U, Lazarus MB, McKenzie KM, Johnston DG, Austin DJ, Ehrlich BE. Paclitaxel induces calcium oscillations via an inositol 1,4,5-trisphosphate receptor and neuronal calcium sensor 1-dependent mechanism. Proc Natl Acad Sci USA, 103(48), 18356-18361 (2006)
- Rengifo, J., C.J. Gibson, E. Winkler, T. Collin, B.E. Ehrlich. Regulation of the Inositol (1,4,5)-Trisphosphate Receptor by O-GlcNAc Glycosylation. Journal of Neuroscience 27: 13813-13821 (2007).
- Heidrich, F.M., M. Estrada, Y., Huang, F.J. Giordano and B.E. Ehrlich. Chromogranin B regulates Ca2+ dependent and NF-kappaB mediated myocardial hypertrophic growth. Circulation Research 102(10):1230-8 (2008).
- Petri, E.T., Ćelić, A., Kennedy, S.D., Ehrlich, B.E., Boggon T.J. & Hodsdon, M.E. Structure of the EF-hand domain of polycystin-2 suggests a mechanism for Ca2+-dependent regulation of polycystin-2 channel activity. Proceedings of the National Academy of Sciences, U.S.A., 107(20): 9176-81 (2010).
- Mo, M., Erdelyi, I., Szigeti-Buck, K., Benbow, J.H. and Ehrlich, B.E. Prevention of paclitaxel- induced peripheral neuropathy by lithium pretreatment. FASEB J., 26(11):4696-709 (2012).
- Kuo, I.Y., DesRochers, T.M., Kimmerling, E.P., Nguyen. L., Ehrlich, B.E., & Kaplan, D.L. Cyst formation following disruption of intracellular calcium signaling. Proceedings of the National Academy of Sciences, 111(39):14283-8 (2014).
- Kuo, I.Y., Kwaczala, A.T., Nguyen, L., Russell, K.S., Campbell, S.G. & Ehrlich, B.E. (2014). Decreased polycystin 2 expression alters calcium-contraction coupling and changes beta-adrenergic signaling pathways. Proceedings of the National Academy of Sciences, 111(46):16604-9 (2014)