Ph.D., SUNY at Buffalo, 1997
neuronal excitability, neurobiology, rhythmic behavior, ion channels, calcium signaling, mammalian fertilization
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 extracellular 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.
on Ion Channel Function in Metabolism, Lysosomal Physiology and mTOR Signaling
Cang, C.*, Zhou, Y.*, Navarro, B., Aranda, K., Shi, L., Battaglia-Hsu, S., Nissim, I., Clapham, D. and Ren, D. (2013) mTOR Regulates Lysosomal ATP-sensitive Two-Pore Na+ Channels to Adapt to Metabolic State. Cell 152: 778-790 (http://www.ncbi.nlm.nih.gov/pubmed/23394946)
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. (2012) TPC proteins are phosphoinositide-activated sodium-selective ion channels in endosomes and lysosomes. Cell 151:372-383 (http://www.ncbi.nlm.nih.gov/pubmed/23063126)
on Ion Channel Function in Rhythmic Behavior, Neuronal Excitability and G Protein-independent GPCR Signaling
Ren, D. (2011) Sodium leak channels in neuronal excitability and rhythmic behaviors. Neuron 72: 899-911. (http://www.ncbi.nlm.nih.gov/pubmed/22196327)
Lu B, Zhang Q, Wang H, Wang Y, Nakayama M, Ren D (2010) Extracellular Calcium Controls Background Current and Neuronal Excitability via an UNC79-UNC80-NALCN Cation Channel Complex. Neuron 68:488-499 (http://www.ncbi.nlm.nih.gov/pubmed/21040849)
Lu, B.*, Su, Y.*, Das, S., Wang, H., Wang, Y., Liu, J. and Ren, D. (2009) Peptide neurotransmitters activate a cation channel complex of NALCN and UNC-80. Nature 457:741-744 (http://www.ncbi.nlm.nih.gov/pubmed/19092807)
Lu, B., Su, Y., Das, S., Xia, J., Liu, J. and Ren, D. (2007) The neuronal NALCN channel contributes resting sodium permeability and is required for normal respiratory rhythm. Cell 129: 371-378. (http://www.ncbi.nlm.nih.gov/pubmed/17448995)
on Ion Channel Function in Mammalian Fertilization, Gamete Interaction and Calcium Signaling
Lishko, P., Kirichok, Y., Ren, D., Navarro, B., Chung, J.-J., and Clapham, D.E. (2011) The control of male fertility by spermatozoan ion channels. Annu. Rev. Physiol. 74: 453-475
Ren, D. (2011) Calcium signaling in sperm: help from prostasomes. Sci Signal 4: pe27
Ren D. (2010) Sperm and the proton channel. N Engl J Med 362: 1934-5
Ren D. and Xia J. (2010) Calcium signaling through CatSper channels in mammalian fertilization. Physiology 25: 165-75
Tang, Q.-Y., Zhang, Z., Xia, J., Ren, D. and Logothetis, D.E. (2010) Phosphatidylinositol (4,5)-bisphosphate (PIP2) activates Slo3 currents and its hydrolysis underlies the EGF-induced current inhibition. J. Biol. Chem. 285: 19259-19266
Xia, J. and Ren, D. (2009) Egg coat proteins activate Ca2+ entry into mouse sperm via CatSper channels. Biol. Reprod. 80:1092-1098
Xia, J. and Ren, D. (2009) CATSPER channels contribute the BSA-induced Ca2+ influx during sperm capacitation. Reprod. Biol. Endocrinol. 7:119.
Wang, H., Liu, J., Cho, K-H. and Ren, D. (2009) A novel, single transmembrane protein CATSPERG is associated with CATSPER1 channel protein. Biol. Reprod. 81: 539-544
Xia, J., Reigada, D., Mitchell, C.H. and Ren, D. (2007) CATSPER channel-mediated Ca2+ entry into mouse sperm triggers a tail-to-head propagation. Biol. Reprod. 77: 551-559
Liu, J., Xia, J., Cho, K-H., Clapham, D.E. and Ren, D. (2007) CatSperβ, a novel transmembrane protein in the CatSper channel complex. J. Biol. Chem. 282: 18945-18952.
Ren, D., Navarro, B., Xu, H., Yue, L., Shi, Q. and Clapham, D.E. (2001) A prokaryotic voltage-gated sodium channel. Science 294: 2372-2375.
Ren, D., Navarro, B., Perez, G., Jackson, A.C., Hsu, S., Shi, Q., Tilly, J.L. and Clapham, D.E. (2001) A sperm ion channel required for sperm motility and male fertility. Nature 413:603-609.