The Ren lab (PI: Dejian Ren, Professor of Biology, contact: dren AT upenn.edu) is associated with the Department of Biology, University of Pennsylvania, and is located at Carolyn Lynch Research Building. The lab currently has two areas of research: 1) neuronal excitability and its implication in intellectual disability, and 2) lysosomal biology and its role in neurodegenerative diseases.
Excitability of the Brain
We study how the intrinsic excitability of mammalian neurons is regulated. A current focus is on the NALCN -UNC80-UNC79 protein complex that we discovered to form the major Na+-leak channel in mammalian brains. NALCN controls the resting membrane potential of neurons and generates heterogeneity in neuronal excitability. Extracellular Na+ , Ca2+ and small neuropeptide such as substance P also excite neurons through NALCN. The complex evolved about more than a billion years ago, before the divergence between fungi and animals, and before the emergence of eukaryotic voltage-gated sodium channels. In collaboration with clinicians and geneticists, we and others found that variations in NALCN and UNC80 genes cause symptoms including hypotonia, lack of speech development, sleep disturbance and severe intellectual disabilities (read more).
Biophysics and Physiology of Endosomes and Lysosomes
Another area of our current research focuses on intracellular organelles. Intracellular membranes constitute >90% of total cell membrane in eukaryotic cells, but their properties are generally less well defined in comparison with plasma membrane. In the past several years, we have used biophysical, biochemical, genetic and structural approaches to define the biophysical and physiological properties of endosomal and lysosomal membranes. Lysosomes are involved in numerous physiological and pathological functions such as digestion, recycling, autophagy, nutrient sensing, exocytosis, wound healing, calcium signaling, neuronal degeneration and gene expression. Surprisingly, we found that some lysosomes have their own voltage-gated sodium channel (TPC1), are electrically excitable and generate action-potential-like spikes when stimulated. We have discovered lysosomal ion channels that are sensitive to luminal pH, voltage across organelle membrane, membrane lipids, cytosolic ATP levels and extracellular nutrient availability. They regulate cellular processes such as autophagosome-lysosome fusion and organismal function such as physical endurance (read more).
Recent genetic studies have implicated lysosomal function in neurodegenerative diseases. For example, variations in the TMEM175 K+ channel we identified are associated with the susceptibility and onset of Parkinson’s disease.
Ion Channel Genes
Sodium/calcium channels: In mammalian brains, voltage-gated Na+ channels (NaVs) and Ca2+ channels (CaVs) are fundamental in action potential generation, synaptic transmission, gene expression and neuronal computation. The pore-forming subunits (α) of CaVs and NaVs consist four homologous repeats, each with six transmembrane domains (6TM, S1-S6). This 4x6TM structure is believed to have evolved from a single 6TM protein through two rounds of gene duplication. In the past, we have discovered 6TM, 2x6TM and 4x6TM ion channels along this evolutionary trajectory.
Potassium channels: Potassium channels play many fundamental roles including setting the resting membrane potential of cells and determining the duration of action potentials in neurons and cardiac muscles. The human genomes have >80 genes encoding the pore-forming subunits of “canonical” K+ channels. A common feature among them is the selectivity filter formed by membrane re-entrant “P-loops” containing a GYG/GFG K+ channel. We recently discovered a novel K+-selective channel TMEM175 (see Cang et al. Cell, 2015). TMEM175 has no P-loop or GYG motif. Instead, the channel filter is formed by the first transmembrane domains (TM1). Homologs are found in bacteria, archaea and eukaryotes. The presence of TMEM175s in all the three life domains suggests an early evolution of two groups of K+ channels with totally different structures: one (as found in the >80 canonical K+ channels) with a GYG/GFG motif-containing P-loop to form the channel pore to select K+ ion, the other (TMEM175) with a P-loop-independent mechanism for K+-selectivity.
Earlier research in the lab also discovered Ca2+ signaling mechanisms during mammalian fertilization (link), with focus on the CatSper ion channel complex in sperm.
Reviews on ion channels we have discovered and/or studied: CatSper (CatSperβ, CatSperγ) (review), NALCN (UNC79, UNC80) (review), TPCs (TPC1, TPC2, TPC3) and KEL/TMEM175 (review).