Cell is composed of around 70% water with a plasma membrane also permeable to water. So keeping cell volume constant in response to osmotic challenges is fundamental to life. This is achieved in mammals by maintaining a stable blood plasma osmolarity (near 300 mOsm/L) and by possessing a variety of mechanisms that allow individual cells to monitor and recover their volume following osmotic swelling or shrinkage. Defective osmoregulation leads to various human disorders, including dehydration, hypertension, renal and neurological diseases. However, the identity of many key osmosensing molecules has been a long-standing mystery. Our goal is to elucidate the molecular mechanisms of mammalian osmotic regulation at both the cellular and whole body levels. We recently performed a genome-wide RNAi screen and co-discovered SWELL1 (LRRC8A) as an essential component of the elusive Volume-Regulated Anion Channel (VRAC) (learn more). VRAC is required for maintaining cell volume in response to osmotic swelling. This discovery enables exciting studies elucidating the function of this important channel in cell volume regulation, fluid secretion, and diseases such as diabetes, stroke and traumatic brain injury.
Deorphanizing the Human Transmembrane Genome: A Focus on Novel Ion Channels
The sequencing of the human genome has fueled the last two decades of work to functionally decipher genome content. An important subset (~25%) of genes encodes transmembrane proteins, which represent the targets of over half of known drugs. Despite recent progress, a large number (~1,500) of membrane proteins are still functionally uncharacterized. We focus on deorphanizing a particularly interesting functional class of membrane proteins, i.e. ion channels or transporters, many of which are well characterized biophysically yet lack underlying molecular identity. Toward this end, we are combining the powerful genomics tools (including bioinformatics, proteomics, single-cell RNA sequencing, and RNAi/CRISPR gene manipulation) with electrophysiology and imaging techniques. Our study will shed light on the molecular identity and physiological function of new pore-forming membrane proteins and may provide therapeutic strategies to target them for diseases with abnormal ion transport and homeostasis.
The Qiu Lab employs a multidisciplinary approach including high-throughput functional genomics, electrophysiology, biochemistry and mouse genetics to discover novel ion channels and to elucidate their role in health and disease. Ion channels are pore-forming membrane proteins gating the flow of ions across the cell membrane. Among their many functions, ion channels regulate cell volume, control epithelial fluid secretion and generate the electrical impulses in our brains.
Lab Website: Qiu Lab
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Osei-Owusu J, Yang J, Vitery MDC, Tian M, Qiu Z., “PAC proton-activated chloride channel contributes to acid-induced cell death in primary rat cortical neurons.” Channels 2020. doi: 10.1080/19336950.2020.1730019.
Yang J*, Chen J*, Vitery MDC*, Osei-Owusu J, Chu J, Yu H, Sun S, Qiu Z. “PAC, an evolutionarily conserved membrane protein, is a proton-activated chloride channel.” Science 2019, 364:395-399. doi: 10.1126/science.aav9739. *Equal contribution.
Yang J, Vitery MDC, Chen J, Osei-Owusu J, Chu J, Qiu Z. “Glutamate-releasing SWELL1 channel in astrocytes modulates synaptic transmission and promotes brain damage in stroke.” Neuron 2019. doi: 10.1016/j.neuron.2019.03.029.
Osei-Owusu J, Yang J, Vitery MDC, Qiu Z. “Molecular Biology and Physiology of Volume-Regulated Anion Channel (VRAC).” Current Topics in Membranes 2018, 81:177-203. doi: 10.1016/bs.ctm.2018.07.005.
Kefauver JM, Saotome K, Dubin AE, Pallesen J, Cottrell CA, Cahalan SM, Qiu Z, Hong G, Crowley CS, Whitwam T, Lee WH, Ward AB, Patapoutian A. “Structure of the human volume regulated anion channel.” eLife 2018. doi: 10.7554/eLife.38461.