KEY WORDS: neuronal excitability, neurobiology, rhythmic behavior, ion channels, calcium signaling
RESEARCH INTERESTS: A current major interest of mine is to uncover the molecular mechanisms underlying the control of neuronal excitability and animal physiology by extracelular ions and peptide neurotransmitters.
RESEARCH TECHNIQUES: electrophysiology, molecular biology, protein chemistry, mouse genetics, live cell imaging.
RESEARCH SUMMARY: Cellular excitability influences essentially every aspect of life, from fertilization to breathing and heart beating. The major interests of the lab concern the regulation of cellular excitability, neuronal network activity and animal behavior by ion channels, G-protein coupled receptors, tyrosine kinases and calcium signaling.
A recent focus in the lab is to study the molecular mechanisms of neuronal excitability control by extracelular ions and peptide neurotransmitters. Significant changes in extracellular Ca2+ concentrations ([Ca2+]e) can happen in certain brain areas during physiological and pathological conditions such as seizures and brain ischemia. We are interested in understanding at the molecular level how neurons sense the [Ca2+]e changes, how the information is transmitted to the intracellular second messenger system, and how neuronal circuit function is affected by the signaling. Numerous neuropeptides are used by the nervous systems as chemical signals to regulate physiological processes such as feeding, rewarding, pain sensation, arousal and wakefulness. We are interested in how several neuropeptides influence the electrical properties of individual neurons in various brain regions and spinal cord. Along this line, we discovered a novel ion channel activation mechanism by G-protein coupled receptors: it is independent of G-protein activation but requires the Src family of tyrosine kinases and two largely uncharacterized proteins UNC79 and UNC80 (see Lu et al. (2009, 2010)). Current efforts in this project focus on uncovering how the receptor activation is coupled to channel opening and how such signaling events contribute to the intrinsic properties of neurons under physiological and pathophysiological conditions.
Another area of research in the lab concerns rhythm generation. All animals display long-period rhythmic behaviors such as circadian rhythm (~ 24 hours), as well as ones with shorter periods such as locomotion, heart beating, and breathing (milliseconds to seconds). We are interested in the molecular mechanisms underlying the generation and modulation of the "short-period" rhythms (Lu et al. (2007), Ren (2011)).
We use an integrative approach to study the physiological problems. At the molecular level, we use molecular biology and protein chemistry to study channel proteins and their associated partners. We use electrophysiology methods to record the electrical activities from a single molecule (single channel recording), a whole cell, or a nerve bundle. At the cellular level, we use high-speed fluorescence confocal microscopy to image dynamics of ions and protein molecules inside the cells. At the systems level, we modify the genomes of animals and study the consequences of such modifications on whole organism physiology and behavior.
Cang, C., Aranda, K., Seo, Y.-J., Gasnier, B. and Ren, D. : TMEM175 is an organelle K+ channel regulating lysosomal function. Cell 162: 1101-1112, 2015.
Flourakis, M., Kula-Eversole, E., Hutchison, A.L., Han, T.H, Aranda, K., Moose, D.L., White, K.P., Dinner, A.R., Lear, B.C., Ren, D, Diekman, C.D., Raman, I.M., and Allada, R.: A Conserved bicycle model for circadian clock control of membrane excitability. Cell 162: 836-848, 2015.
Xu, H. and Ren, D.: Lysosomal Physiology. Annu. Rev. Physiol. 77: 57-80, 2015.
Cang, C., Bekele, B. and Ren, D. : The voltage-gated sodium channel TPC1 confers endolysosomal excitability. Nature Chem. Biol. 10: 436-469, 2014.
Cang, C.*, Zhou, Y.*, Navarro, B., Seo, Y.-J., Aranda, K., Shi, L., Battaglia-Hsu, S., Nissim, I., Clapham, D.E. and Ren, D. : mTOR regulates lysosomal ATP-sensitive two-pore Na+ channel to adapt to metabolic state. Cell 152: 778-790, 2013.
Wang, X., Zhang, X., Dong, X.-P., Samie, M., Li, X., Cheng, X., Goschka, A., Shen, D., Zhou, Y., Harlow, J., Zhu, M.-X., Clapham, D.E., Ren, D., and Xu, H. : TPC proteins are phosphoinositide-activated sodium-selective ion channels in endosomes and lysosomes. Cell 151: 372-383, 2012.
Ren, D.: Sodium leak channels in neuronal excitability and rhythmic behaviors. Neuron 72: 899-911, 2011.
Lu B, Zhang Q, Wang H, Wang Y, Nakayama M, Ren D.: Extracellular Calcium Controls Background Current and Neuronal Excitability via an UNC79-UNC80-NALCN Cation Channel Complex. Neuron 68: 488-499, 2010.
Lu, B.*, Su, Y.*, Das, S., Wang, H., Wang, Y., Liu, J., and Ren, D. : Peptide neurotransmitters activate a cation channel complex of NALCN and UNC-80. Nature 457: 741-744 (Epub 2008 Dec 17), 2009.
Lu, B., Su, Y., Das, S., Liu, J., Xia, J. and Ren, D. : The neuronal channel NALCN contributes resting sodium permeability and is required for normal respiratory rhythm. Cell 129: 371-383, 2007.
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Last updated: 11/03/2015
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